Substituted heteroaryl compounds and methods of use

ABSTRACT

The present invention provides novel heteroaryl compounds, pharmaceutical acceptable salts and formulations thereof. They are useful in preventing, managing, treating or lessening the severity of a protein kinase-mediated disease. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of protein kinase-mediated disease.

CROSS-REFERENCE TO RELATED APPLICATION

The is a divisional application of U.S. application Ser. No. 15/257,926,filed on Sep. 7, 2016, which claims the benefit of U.S. ProvisionalApplication Ser. No. 62/217,676, filed on Sep. 11, 2015, both of whichare hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention provides novel substituted aminopyrimidinecompounds, and salts thereof, which are useful in the treatment ofproliferative disease, autoimmune disease, allergic disease,inflammatory disease, transplantation rejection, and other diseases, inmammals. In particular, this invention relates to compounds thatmodulate the activity of JAK kinases, FLT3 kinase, and Aurora kinasesresulting in the modulation of inter- and/or intra-cellular signaling.This invention also relates to a method of using such compounds in thetreatment of proliferative disease, autoimmune disease, allergicdisease, inflammatory disease, transplantation rejection, and otherdiseases in mammals, especially humans, and to pharmaceuticalcompositions containing such compounds.

BACKGROUND OF THE INVENTION

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within the cell. Protein kinases, containing asimilar 250-300 amino acid catalytic domain, catalyze thephosphorylation of target protein substrates. It is reported that manydiseases are associated with abnormal cellular responses triggered byprotein kinase-mediated events. These diseases include benign andmalignant proliferation disorders, diseases resulting from inappropriateactivation of the immune system, allograft rejection, graft vs hostdisease, autoimmune diseases, inflammatory diseases, bone diseases,metabolic diseases, neurological and neurodegenerative diseases, cancer,cardiovascular diseases, allergies and asthma, Alzheimer's disease andhormone-related diseases. Accordingly, there has been a substantialeffort in medicinal chemistry to find protein kinase inhibitors that areeffective as therapeutic agents.

The kinases may be categorized into families by the substrates in thephosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids,etc.). Tyrosine phosphorylation is a central event in the regulation ofa variety of biological processes such as cell proliferation, migration,differentiation and survival. Several families of receptor andnon-receptor tyrosine kinases control these events by catalyzing thetransfer of phosphate from ATP to a tyrosine residue of specific cellprotein targets. Sequence motifs have been identified that generallycorrespond to each of these kinase families (Hanks et al., FASEB J.,1995, 9, 576-596; Knighton et al., Science, 1991, 253, 407-414;Garcia-Bustos et al., EMBO J., 1994, 13:2352-2361). Some non-limitingexamples of the protein kinase include abl, Aurora, Akt, bcr-abl, BIk,Brk, Btk, c-kit, c-Met, c-src, c-fms, CDK1, CDK2, CDK3, CDK4, CDK5,CDK6, CDK7, CDK8, CDK9, CDK10, cRafl, CSF1 R, CSK, EGFR, ErbB2, ErbB3,ErbB4, Erk, Fak, fes, Flt-3, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr,Flt-1, Fps, Frk, Fyn, Hck, IGF-1 R, INS-R, JAK, KDR, Lck, Lyn, MEK, p38,PDGFR, PIK, PKC, PYK2, ros, Tie, Tie-2, TRK, Yes, and Zap70.

Aurora kinase family is a collection of highly related serine/threoninekinase that are key regulators of mitosis, essential for accurate andequal segtion of genomic material from parent to daught cells. Membersof the Aurora kinase family include three related kinases known asAurora-A, Aurora-B, and Aurora-C (also known as Aurora-1, Aurora-2, andAurora-3). Despite significant sequence homology, the localization andfunctions of these kinases are largely distinct from one another(Richard D. Carvajal, et al. Clin. Cancer Res., 2006, 12(23): 6869-6875;Daruka Mahadevan, et al., Expert Opin. Drug Discov., 2007 2(7):1011-1026).

Aurora-A is ubiquitously expressed and regulates cell cycle eventsoccurring from late S phase through M phase, including centrosomematuration, mitotic entry, centrosome separation, bipolar-spindleassembly, chromosome alignment on the metaphase plate, cytokinesis andmitotic exit. Aurora-A protein levels and kinase activity both increasefrom late G2 through M phase, with peak activity in prometaphase. Onceactivated, Aurora-A mediates its multiple functions by interacting withvarious substrates including centrosome, transforming acidic coiled-coilprotein, cdc25b, Eg5, and centromere protein A.

Aurora-B is a chromosomal passenger protein critical for accuratechromosomal segregation, cytokinesis, protein localization to thecentromere and kinetochore, correct microtubule-kinetochore attachmentsand regulation of the mitotic checkpoint. Aurora-B localizes first tothe chromosomes during prophase and then to the inner centromere regionbetween sister chromatids during prometaphase and metaphase (Zeitlin SG, et al. J. Cell. Biol., 2001, 155:1147-1157). Aurora-B participates inthe establishment of chromosomal biorientation, a condition where sisterkinetochores are linked to opposite poles of the bipolar spindle viaamphitelic attachments. The primary role of Aurora-B at this point ofmitosis is to repair incorrect microtubule-kinetochore attachments (HaufS, et al., J. Cell Biol., 2003, 161: 281-294; Ditchfield C, et al., J.Cell Biol., 2003, 161:267-280; Lan W, et al. Curr. Biol., 2004,14:273-286). Without Aurora-B activity, the mitotic checkpoint iscompromised, resulting in increased numbers of aneuploid cells, geneticinstability, and tumorigenesis (Weaver B A, et al., Cancer Cell., 2005,8:7-12).

Aurora-A overexpression is a necessary feature of Aurora-A inducedtumorigenesis. In cells with Aurora-A overexpression, mitosis ischaracterized by the presence of multiple centrosomes and multipolarspindles (Meraldi P et al., EMBO J., 2002, 21:483-492). These cells failto undergo cytokinesis, and, with additional cell cycles, polyploidy andprogressive chromosomal instability develop (Anand S, et al., CancerCell, 2003, 3:51-62).

The evidence linking Aurora overexpression and malignancy proliferationdisorders, such as colon, breast, lung, pancrease, prostate, bladder,head, neck, cervix, and ovarian cancers, liver, gastric and pancreatictumors, has stimulated interest in developing Aurora inhibitors forcancer therapy. In normal cells, Aurora-A inhibition results in delayed,but not blocked, mitotic entry, centrosome separation defects resultingin unipolar mitotic spindles, and failure of cytokinesis (Marumoto T, etal., J. Biol. Chem., 2003, 278:51786-51795). Encouraging antitumoreffects with Aurora-A inhibition were shown in three human pancreaticcancer cell lines (Panc-1, MIA PaCa-2, and SU.86.86), with growthsuppression in cell culture and near-total abrogation of tumorigenicityin mouse xenografts (Hata T, et al., Cancer Res., 2005, 65:2899-2905).

Aurora-B inhibition results in abnormal kinetochore-microtubuleattachments, failure to achieve chromosomal biorientation, and failureof cytokinesis (Goto H, et al., J. Biol. Chem., 2003, 278:8526-30;Severson AF₁ et al., Curr. Biol., 2000, 10:1162-1171). Recurrent cyclesof aberrant mitosis without cytokinesis result in massive polyploidyand, ultimately, to apoptosis (Hauf S, et al., J. Cell Biol., 2003,161:281-294; Ditchfield C, et al., J. Cell Biol., 2003, 161:267-80; GietR, et al., J. Cell Biol., 2001, 152:669-682; Murata-Hori M, Curr. Biol.,2002, 12:894-899; Kallio M J, et al., Curr. Biol., 2002, 12:900-905).

Inhibition of Aurora-A or Aurora-B activity in tumor cells results inimpaired chromosome alignment, abrogation of the mitotic checkpoint,polyploidy, and subsequent cell death. These in vitro effects aregreater in transformed cells than in either non-transformed ornon-dividing cells (Ditchfield C, et al., J. Cell Biol., 2003,161:267-280). Thus, targeting Aurora may achieve in vivo selectivity forcancer. Although toxicity to rapidly dividing cell of the hematopoieticand gastrointestinal system is expected, the activity and clinicaltolerability shown in xenograft models indicates the presence of areasonable therapeutic index. Given the preclinical antitumor activityand potential for tumor selectivity, several Aurora kinase inhibitorshave been developed.

FLT3 (Flt3, FMS-related tyrosine kinase 3), also known as FLK-2 (fetalliver kinase 2) and STK-1 (human stem cell kinase 1), belongs to amember of the class III receptor tyrosine kinase (RTK-III) family thatinclude KIT, PDGFR, FMS and FLT1 (Stirewalt D L, et al., Nat. Rev.Cancer, 2003, 3:650-665; Rosnet O, et al., Genomics 1991, 9:380-385;Yarden Y, et al., Nature, 1986, 323: 226-232; Stanley E R, et. al., J.Cell. Biochem., 1983, 21:151-159; Yarden Y, et al., EMBO J., 1987,6:3341-3351). FLT3 is a membrane-spanning protein and composed of fourdomains; an extracellular ligand-binding domains consisting of fiveimmunoglobin-like structures, a transmembrane (TM) domain, ajuxtamembrane (JM) domain and a cytoplasmic C-Terminal tyrosine kinase(TK) domain (Agnes F, et al., Gene, 1994, 145:283-288, Scheijen B, etal., Oncogene, 2002, 21: 3314-3333).

The ligand for FLT3 (FLT3 or FL) was cloned in 1993 and shown to be aType I transmembrane protein expressed in cells of the hematopoieticbone marrow microenvironment, including bone marrow fibroblasts andother cells (Lyman S D, et al., Cell 1993, 75:1157-1167). Both themembrane-bound and soluable forms can activate the tyrosine kinaseactivity of the receptor and stimulate growth of progenitor cells in themarrow and blood. Binding of ligand to receptor induces dimerisation ofthe receptor and activation of the kinase domains; which thenautophosphorylate and catalyse phosphorylation of substrate proteins ofvarious signal transduction pathways such as signal transducer andactivator of STAT5, RAS/MAPK, PI3K, SHC, SHIP, and SHP2, which playimportant roles in cellular proliferation, differentiation, and survival(Dosil M, et al., Mol. Cell Biol., 1993, 13:6572-6585. Zhang S, Biochem.Biophys. Res. Commun., 1999, 254:440-445). In addition to hemotopoieticcells, FLT3 gene is also expressed in placenta, gonads and brain (MarocN, et al., Oncogene, 1993, 8: 909-918) and also plays an import and rolein the immune response (deLapeyriere O, et al., Leukemia, 1995,9:1212-1218).

FLT3 has also been implicated in hematopoietic disorders which arepre-malignant disorders including myeloproliferative disorders, such asthrombocythemia, essential thrombocytosis (ET), myelofibrosis (MF),chronic idiopathic myelofibrosis (IMF), and polycythemia vera (PV),pre-malignant myelodysplastic syndromes. Hematological malignanciesinclude leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease(also called Hodgkin's lymphoma), and myeloma, for instance, acutelymphocytic leukemia (ALL), acute myeloid leukemia (AML), acutepromyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL).FLT3 is overexpressed at the levels in 70-100% of cases of acute myeloidleukemias (AML), and in a high percentage of T-acute lymphocyticleukemia (ALL) cases (Griffin J D, et al., Haematol J. 2004, 5:188-190). It is also overexpressed in a smaller subset of chronicmyeloid leukemia (CML) in blast crisis. Studies have shown that theleukemic cells of B lineage ALL and AML frequently co-express FLT3,setting up autocrine or paracrine signaling loops that result in theconstitutive activation of FLT3 (Zheng R, et. al., Blood., 2004, 103:267-274). A high level of the FLT3 ligand is found in the serum ofpatients with Langerhans cell histocytosis and systemic lupuserythematosus, which further implicates FLT3 signaling in thedysregulation of dendritic cell progenitors in those autoimmune diseases(Rolland et al., J. Immunol., 2005, 174:3067-3071).

Evidence is rapidly accumulating that many types of leukemias andmyeloproliferative syndromes have mutation in tyrosine kinases. FLT3mutations are one of the most frequent somatic alterations in AML,occurring in approximately ⅓ of patients. There are two types ofactivating mutations in FLT3 described in patients with leukemia. Theseinclude a spectrum of internal tandem duplications (ITD) occurringwithin the auto-inhibitory juxtamembrane domain (Nakao M, et al.,Leukemia, 1996, 10:1911-1918; Thiede C, et al., Blood, 2002,99:4326-4335), and activation loop mutations that include Asp835Tyr(D835Y), Asp835Val (D835V), Asp835His (D835H), Asp835Glu (D835E),Asp835Ala (D835A), Asp835Asn (D835N), Asp835 deletion and Ile836deletion (Yamamoto Y₁ et al., Blood 2001, 97:2434-2439; Abu-Duhier F M,et al., Br. J. Haematol., 2001, 113:983-988). Internal tandemduplication (ITD) mutations within the JM domain contribute to about17-34% of FLT3 activating mutations in AML. FLT3-ITD has also beendetected at low frequency in myelodysplastic syndrome (MDS) (Yokota S,et al., Leukemia, 1997, 11:1605-1609; Horiike S, et al., Leukemia, 1997,11:1442-1446). Both FLT3-ITD and FLT3-Asp835 mutations are associatedwith FLT3 autophosphorylation and phosphorylation of downstream targets(Mizuki M, et al., Blood, 2000, 96:3907-3914; Mizuki M, et al., Blood,2003, 101:3164-3173; Hayakawa F, et al., Oncogene, 2000, 19: 624-631).

Inhibitors of FLT3 are presently being studied and have reached clinicaltrials as monotherapy in relapsed or refractory AML patients, some orall of whom had FLT3 mutations. Collectively, these data suggest thatFLT3 is an attractive therapeutic target for the development of kinaseinhibitors for AML and other associated diseases.

Janus kinase (JAK) is a family of intracellular, non-receptor tyrosinekinases that transduce cytokine-mediated signals via the JAK-STATpathway. The JAK family plays a role in the cytokine-dependentregulation of proliferation and function of cells involved in immuneresponse. Cytokines bind to their receptors, causing receptordimerization, and this enables JAKs to phosphorylate each other as wellas specific tyrosine motifs within the cytokine receptors. STATs thatrecognize these phosphotyrosine motifs are recruited to the receptor,and are then themselves activated by a JAK-dependent tyrosinephosphorylation event. Upon activation, STATs dissociate from thereceptors, dimerize, and translocate to the nucleus to bind to specificDNA sites and alter transcription.

Currently, there are four known mammalian JAK family members: JAK1(Janus kinase-1), JAK2 (Janus kinase-2), JAK3 (Janus kinase, leukocyte;JAKL; L-JAK and Janus kinase-3) and TYK2 (protein-tyrosine kinase 2).While JAK1, JAK2 and TYK2 are ubiquitously expressed, JAK3 is reportedto be preferentially expressed in natural killer (NK) cells and notresting T cells (“Biology and significance of the JAK/STAT signalingpathways.” Growth Factors, April 2012; 30(2): 88).

JAK1 is essential for signaling for certain type I and type IIcytokines. It interacts with the common gamma chain (γc) of type Icytokine receptors to elicit signals from the IL-2 receptor family, theIL-4 receptor family, the gp130 receptor family. It is also importantfor transducing a signal by type I (IFN-α/β) and type II (IFN-γ)interferons, and members of the IL-10 family via type II cytokinereceptors. Genetic and biochemical studies have shown that JAK1 isfunctionally and physically associated with the type I interferon (e g.,IFNalpha), type II interferon (e.g., IFNgamma), IL-2 and IL-6 cytokinereceptor complexes. Furthermore, characterization of tissues derivedfrom JAK1 knockout mice demonstrated critical roles for this kinase inthe IFN, IL-IO, IL-2/IL-4, and IL-6 pathways.

Expression of JAK1 in cancer cells enables individual cells to contract,potentially allowing them to escape their tumor and metastasize to otherparts of the body. Elevated levels of cytokines which signal throughJAK1 have been implicated in a number of immune and inflammatorydiseases. JAK1 or JAK family kinase inhibitors may be useful formodulating or treating in such diseases. (Kisseleva et al., Gene, 2002,285:1-24; Levy et al., Nat. Rev. Mol. Cell Biol., 2005, 3:651-662). Ahumanized monoclonal antibody targeting the IL-6 pathway (Tocilizumab)was approved by the European Commission for the treatment ofmoderate-to-severe rheumatoid arthritis (Scheinecker et al., Nat. Rev.Drug Discov., 2009, 8:273-274).

JAK2 is implicated in signaling by members of the type II cytokinereceptor family (e.g. interferon receptors), the GM-CSF receptor family,the gp130 receptor family. JAK2 signaling is activated downstream fromthe prolactin receptor. Studies have identified a high prevalence of anacquired activating JAK2 mutation (JAK2V617F) in myleoproliferativedisorders such as polycythemia vera, essential thrombocythemia andidiopathic myelofibrosis, etc. The mutant JAK2 protein is able toactivate downstream signaling in the absence of cytokine stimulation,resulting in autonomous growth and/or hypersensitivity to cytokines andis believed to play a role in driving these diseases. Additionalmutations or translocations resulting dysregulated JAK2 function havebeen described in other malignancies (Ihle J. N. and Gilliland D. G.,Curr. Opin. Genet. Dev., 2007, 17:8; Sayyah J. and Sayeski P. P., Curr.Oncol. Rep., 2009, 11: 117). Inhibitors of JAK2 have been described tobe useful in myeloproliferative diseases (Santos et al, Blood, 2010,115:1131; Barosi G. and Rosti V., Curr. Opin. Hematol, 2009, 16:129,Atallah E. and Versotvsek S., Exp. Rev. Anticancer Ther., 2009, 9:663).

JAK3 associates exclusively with the gamma common cytokine receptorchain, which is present in the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21cytokine receptor complexes. JAK3 is predominantly expressed in immunecells and transduces a signal in response to its activation via tyrosinephosphorylation by interleukin receptors. Since JAK3 expression isrestricted mostly to hematopoietic cells, its role in cytokine signalingis thought to be more restricted than other JAKs. Mutations of JAK3result in severe combined immunodeficiency (SCID). (O'Shea et al., 2002,Cell, 109 (suppl.): S121-S131). Based on its role in regulatinglymphocytes, JAK3 and JAK3-mediated pathways have been targeted forimmunosuppressive indications (e.g., transplantation rejection andrheumatoid arthritis) (Baslund et al., Arthritis & Rheumatism, 2005,52:2686-2692; Changelian et al., Science 2003, 302: 875-878).

TYK2 is implicated in IFN-α, IL-6, IL-10 and IL-12 signaling.Biochemical studies and gene-targeted mice uncovered the crucial role ofTYK2 in immunity. Tyk2-deficient mice are viable and fertile but displaymultiple immunological defects, most prominently high sensitivity toinfections and defective tumor surveillance. In contrast, inhibition ofTYK2 results in increased resistance against allergic, autoimmune andinflammatory diseases. Particularly, targeting Tyk2 appears to be apromising strategy for the treatment of IL-12-, IL-23- or Type 1IFN-mediated diseases. These include but are not limited to rheumatoidarthritis, multiple sclerosis, lupus, psoriasis, psoriatic arthritis,inflammatory bowel disease, uveitis, sarcoidosis, and tumors (Shaw, M.et al., Proc. Natl. Acad. Sci. USA, 2003, 100, 11594-11599; Ortmann, R.A., and Shevach, E. M. Clin. Immunol, 2001, 98, 109-118; Watford et al,Immunol. Rev., 2004, 202: 139). [“Janus Kinase (JAK) Inhibitors inRheumatoid Arthritis.” Current Rheumatology Reviews, 2011, 7, 306-312].

A fully human monoclonal antibody targeting the shared p40 subunit ofthe IL-12 and 11-23 cytokines (Ustekinumab) was recently approved by theEuropean Commission for the treatment of moderate-to-severe plaquepsoriasis (Krueger et al., N Engl. J. Med., 2007, 356:580-92; Reich etal., Nat. Rev. Drug Discov., 2009, 8:355-356). In addition, an antibodytargeting the IL-12 and IL-23 pathways underwent clinical trials fortreating Crohn's Disease (Mannon et al., N. Engl. J. Med., 2004, 351:2069-79).

When dysregulated, JAK-mediated responses can positively or negativelyaffect cells leading to over-activation and malignancy or immune andhematopoietic deficiencies, respectively, and suggests the utility foruse of inhibitors of JAK kinases. The JAK/STAT signaling pathway isinvolved in a variety of hyperproliferative and cancer-related processesincluding cell-cycle progression, apoptosis, angiogenesis, invasion,metastasis and evasion of the immune system (Haura et al., NatureClinical Practice Oncology, 2005, 2(6), 315-324; Verna et al., Cancerand Metastasis Reviews, 2003, 22, 423-434). In addition, the JAK/STATsignaling pathway is important in the genesis and differentiation ofhematopoietic cells and regulating both pro- and anti-inflammatory andimmune responses (O' Sullivan et al., Molecular Immunology 2007,44:2497).

Therefore, the JAK/STAT pathway, and in particular all four members ofthe JAK family, are believed to play a role in the pathogenesis of theasthmatic response, chronic obstructive pulmonary disease, bronchitis,and other related inflammatory diseases of the lower respiratory tract.The JAK/STAT pathway has also been implicated to play a role ininflammatory diseases/conditions of the eye including, but not limitedto, iritis, uveitis, scleritis, conjunctivitis, as well as chronicallergic responses. Since cytokines utilize different patterns of JAKkinases (O'Sullivan et al., Mol. Immunol, 2007, 44:2497; Murray J.,Immunol, 2007, 178:2623), there may be utility for antagonists of JAKkinases with differing intra-family selectivity profiles in diseasesassociated with particular cytokines or in diseases associated withmutations or polymorphisms in the JAK/STAT pathways.

Rheumatoid arthritis (RA) is an autoimmune disease characterized bychronic joint inflammation. Patients with rheumatoid arthritis treatedwith JAK inhibitor showed that inhibition of JAK1 and JAK3 blockssignalling by multiple cytokines that are important for lymphocytefunction, including interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 andIL-21. (Fleischmann, R. et al., “Placebo-controlled trial of tofacitinibmonotherapy in rheumatoid arthritis.” N. Engl. J. Med., 2012, 367,495-507). It was conjectured that small-molecule inhibitors thatdirectly inactivate specific JAK isoforms would also reduce not only theclinical symptoms of RA, but also suppress the upregulation of many ofthe proinflammatory cytokines that are critical in driving RA diseaseprogression. (“Inhibitors of JAK for the treatment of rheumatoidarthritis: rationale and clinical data.” Clin. Invest., 2012, 2(1),39-47)

Persistent activation of STAT3 or STAT5 has been demonstrated in a widespectrum of solid human tumors including breast, pancreatic, prostate,ovarian and hepatic carcinomas, as well as in the majority ofhematopoietic tumors including lymphomas and leukemias. In this context,inactivation of JAK/STAT signaling in many hematopoietic tumors resultedin inhibition of cell proliferation and/or induction of apoptosis.Although STAT3 in tumor cells can be activated by various kinases, JAK2has been shown to be the most important upstream activator mediatingSTAT3 activation in human tumor cell lines derived from various solidtumors (Mohamad Bassam Sonbol, Belal Firwana, Ahmad Zarzour, MohammadMorad, Vishal Rana and Ramon V. Tiu, Therapeutic Advances in Hematology,2013, 4(1), 15-35; Hedvat M, Huszar D, Herrmann A, Gozgit J M, SchroederA, Sheehy A, et al., Cancer Cell 2009; 16(6):487-97). Therefore,inhibition of JAK kinases may have a beneficial role in the therapeutictreatment of these diseases.

Clearly, protein kinase inhibitors have gathered attention as a new drugcategory for both immunosuppression and antiinflammatory drug, and forcancer drug. Thus, new or improved agents which inhibit protein kinasessuch as Aurora inhibitors, FLT3 inhibitors and Janus kinases inhibitorsare continually needed that act as immunosuppressive agents for organtransplants, and antitumor agents, as well as agents for the preventionand treatment of autoimmune diseases (e.g., multiple sclerosis,psoriasis, rheumatoid arthritis, asthma, type I diabetes, inflammatorybowel disease, Crohn's disease, polycythemia vera, essentialthrombocythemia, myelofibrosis, autoimmune thyroid disorders,Alzheimer's disease), diseases involving a hyperactive inflammatoryresponse (e.g., eczema), allergies, chronic obstructive pulmonarydisease, bronchitis, cancer (e.g., prostate, acute myelogenous leukemia,chronic myelogenous leukemia, acute lymphocytic leukemia, leukemia,multiple myeloma), and some immune reactions (e.g., skin rash or contactdermatitis or diarrhea) caused by other therapeutics, to name a few. Thecompounds, compositions and methods described herein are directed towardthese needs and other ends.

SUMMARY OF THE INVENTION

The invention provides compounds that inhibit, regulate, and/or modulateone or more protein kinases such as JAK, FLT3 and Aurora kinasesactivities, and are useful for treating proliferative diseases,autoimmune diseases, allergic diseases, inflammatory diseases,transplantation rejections, and their co-morbidities. This inventionalso provides methods of making the compound, methods of using suchcompounds in the treatment of said diseases in mammals, especially inhumans, and pharmaceutical compositions containing these compounds. Thecompounds or the pharmaceutical composition disclosed herein have betterprospects for clinical application. Compared with the similar compounds,the compounds disclosed herein have a better pharmacological activity,pharmacokinetic properties, physical and chemical properties and/orlesser toxicity. In particular, the compounds of the present inventiondisplay potent inhibitory activities against target kinases, andoptimized selectivity. In addition, the compounds or the pharmaceuticalcomposition disclosed herein have good membrane permeability andsolubility, and are suitable for topical administration.

Specifically, in one aspect, provided herein is a compound havingFormula (I):

or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, apharmaceutically acceptable salt or a prodrug thereof, wherein each ofZ, Z¹, A and R¹ is as defined herein.

In one embodiment, Z is C₇-C₁₂ spiro bicycloalkyl, C₇-C₁₂ fusedbicycloalkyl, 7-12 membered spiro heterobicyclyl or 7-12 membered fusedheterobicycloalkyl, wherein Z is substituted by 1, 2, 3, 4 or 5 R²groups;

Z¹ is H, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl or 3-12 membered heterocyclyl,wherein each of the C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl and 3-12 memberedheterocyclyl is optionally independently substituted by 1, 2, 3, 4 or 5R^(2a) groups;

A is

R¹ is H, F, Cl, Br, I, N₃, CN, —NO₂, C₁-C₁₂ alkyl, C₁-C₁₂ alkoxyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, 3-12 memberedheterocyclyl, C₆-C₁₂ aryl, 5-12 membered heteroaryl, —NR^(9a)R^(9b),—OR^(9c), —C(═O)OR^(9c), —C(═O)NR^(9a)R^(9b) or —S(═O)₂NR^(9a)R^(9b),wherein each of the C₁-C₁₂ alkyl, C₁-C₁₂ alkoxyl, C₂-C₁₂ alkenyl, C₂-C₁₂alkynyl, C₃-C₁₂ cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryl and5-12 membered heteroaryl is optionally independently substituted by 1,2, 3, 4 or 5 R¹¹ groups;

each R² is independently F, Cl, Br, I, —NO₂, N₃, CN, —OH, —NH₂,—C(═O)CH₂CN, —NHC(═O)CH₂CN, —N(CH₃)C(═O)CH₂CN, C₁-C₁₂ alkyl, C₂-C₁₂alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂ alkoxyl, C₃-C₁₂ cycloalkyl, 3-12membered heterocyclyl, C₆-C₁₂ aryl, 5-12 membered heteroaryl,—NR^(10a)R^(10b), —O—(C₀-C₄ alkylene)-R^(10c), —O—(C₁-C₄alkylene)-OR^(10c), —C(═O)R^(10d), —OC(═O)R^(10d),—N(R^(10e))C(═O)R^(10d), —C(═O)NR^(10a)R^(10b),—N(R^(10e))C(═O)NR^(10a)R^(10b), —C(═O)N(R^(10e))C(═O)R^(10d),—S(═O)₂R^(10f), —N(R^(10e))S(═O)₂R^(10f) or —S(═O)₂NR^(10a)R^(10b), ortwo adjacent R² taken together with the atoms to which they are attachedform a C₃-C₁₂ cycloalkyl or 3-12 membered heterocycloalkyl group,wherein each of the C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂alkoxyl, C₃-C₁₂ cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryl,5-12 membered heteroaryl, and 3-12 membered heterocycloalkyl group isoptionally independently substituted by 1, 2, 3, 4 or 5 R¹¹ groups;

each R^(2a) is independently H, F, Cl, Br, I, —NO₂, N₃, CN, —OH, —NH₂,C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂ alkoxyl, C₃-C₁₂cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryl or 5-12 memberedheteroaryl, wherein each of the C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂alkynyl, C₁-C₁₂ alkoxyl, C₃-C₁₂ cycloalkyl, 3-12 membered heterocyclyl,C₆-C₁₂ aryl, 5-12 membered heteroaryl, and 3-12 memberedheterocycloalkyl group is optionally independently substituted by 1, 2,3, 4 or 5 R¹¹ groups;

R³ is H, C₃-C₁₂ hydroxyalkyl, C₃-C₁₂ alkyl, C₁-C₁₂ haloalkyl, C₁-C₁₂aminoalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, whereineach of the C₃-C₁₂ hydroxyalkyl, C₃-C₁₂ alkyl, C₁-C₁₂ haloalkyl, C₁-C₁₂aminoalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂aryl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl isoptionally independently substituted by 1, 2, 3, 4 or 5 R¹¹ groups;

R⁴ is C₁-C₁₂ hydroxyalkyl, C₃-C₁₂ alkyl, C₁-C₁₂ haloalkyl, C₁-C₁₂aminoalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, wherein R⁴is optionally substituted by 1, 2, 3, 4 or 5 R¹¹ groups;

each of R⁵, R⁶, R⁷ and R⁸ is independently H, C₁-C₁₂ hydroxyalkyl,C₃-C₁₂ alkyl, C₁-C₁₂ haloalkyl, C₁-C₁₂ aminoalkyl, C₂-C₁₂ alkenyl,C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂aryl or 5-12 membered heteroaryl, wherein each of the C₁-C₁₂hydroxyalkyl, C₃-C₁₂ alkyl, C₁-C₁₂ haloalkyl, C₁-C₁₂ aminoalkyl, C₂-C₁₂alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, 3-12 membered heterocyclyl,C₆-C₁₂ aryl and 5-12 membered heteroaryl is optionally independentlysubstituted by 1, 2, 3, 4 or 5 R¹¹ groups;

each R^(3a), R^(4a), R^(5a), R^(6a), R^(7a) and R^(8a) is independentlyH, F, Cl, CN, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂alkoxyl, C₁-C₁₂ alkylamino, —(C₀-C₄ alkylene)-(C₃-C₁₂ cycloalkyl),—(C₀-C₄ alkylene)-(3-12 membered heterocyclyl), C₆-C₁₂ aryl or 5-12membered heteroaryl, wherein each of the C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl,C₂-C₁₂ alkynyl, C₁-C₁₂ alkoxyl, C₁-C₁₂ alkylamino, —(C₀-C₄alkylene)-(C₃-C₁₂ cycloalkyl), —(C₀-C₄ alkylene)-(3-12 memberedheterocyclyl), C₆-C₁₂ aryl and 5-12 membered heteroaryl is optionallyindependently substituted by 1, 2, 3, 4 or 5 R¹¹ groups;

each R^(9a), R^(9b), R^(9c), R^(10a), R^(10b), R^(10c) and R^(10e) isindependently H, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂alkoxyl, C₃-C₁₂ cycloalkyl, —(C₀-C₄ alkylene)-(C₃-C₁₂ cycloalkyl),—(C₀-C₄ alkylene)-(3-12 membered heterocyclyl), —(C₀-C₄alkylene)-(C₆-C₁₀ aryl) or —(C₀-C₄ alkylene)-(5-12 membered heteroaryl),or R^(9a) and R^(9b), R^(10a) and R^(10b) taken together with thenitrogen atom to which they are attached form a 3-12 memberedheterocyclyl group, wherein each of the C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl,C₂-C₁₂ alkynyl, C₁-C₁₂ alkoxyl, C₃-C₁₂ cycloalkyl, —(C₀-C₄alkylene)-(C₃-C₁₂ cycloalkyl), —(C₀-C₄ alkylene)-(3-12 memberedheterocyclyl), —(C₀-C₄ alkylene)-(C₆-C₁₀ aryl), —(C₀-C₄ alkylene)-(5-12membered heteroaryl) and 3-12 membered heterocyclyl group is optionallysubstituted by 1, 2, 3 or 4 substitutents independently selected from F,Cl, Br, CN, N₃, —NO₂, —OH, —NH₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl and C₁-C₆ alkylamino;

each R^(10d) and R^(10f) is independently C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl,C₂-C₁₂ alkynyl, C₁-C₁₂ alkoxyl, C₃-C₁₂ cycloalkyl, 3-12 memberedheterocyclyl, C₆-C₁₂ aryl, 5-12 membered heteroaryl, —(C₁-C₄alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄ alkylene)-(3-12 memberedheterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl) or —(C₁-C₄alkylene)-(5-12 membered heteroaryl), wherein each of the abovesubstituents is optionally substituted by 1, 2, 3 or 4 substitutentsindependently selected from F, Cl, Br, CN, N₃, —OH, —NH₂, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl andC₁-C₆ alkylamino;

each R¹¹ is independently F, Cl, Br, I, CN, —NO₂, N₃, —OH, —NH₂, C₁-C₁₂alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂ haloalkyl, C₃-C₁₂cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl, 5-12 memberedheteroaryl, C₁-C₁₂ aminoalkyl, C₁-C₁₂ alkylamino, C₁-C₁₂ alkoxyl, C₁-C₁₂hydroxyalkyl, —NH(C₀-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —NH(C₀-C₄alkylene)-(C₆-C₁₂ aryl), —NH(C₀-C₄ alkylene)-(3-12 memberedheterocyclyl), —NH(C₀-C₄ alkylene)-(5-12 membered heteroaryl), —N[(C₀-C₄alkylene)-(C₃-C₁₂ cycloalkyl)]₂, —N[(C₀-C₄ alkylene)-(C₆-C₁₂ aryl)]₂,—N[(C₀-C₄ alkylene)-(3-12 membered heterocyclyl)]₂, —N[(C₀-C₄alkylene)-(5-12 membered heteroaryl)]₂, —O—(C₀-C₄ alkylene)-(C₃-C₁₂cycloalkyl), —O—(C₀-C₄ alkylene)-(C₆-C₁₂ aryl), —O—(C₀-C₄alkylene)-(3-12 membered heterocyclyl) or —O—(C₀-C₄ alkylene)-(5-12membered heteroaryl); and

each m is independently 0, 1 or 2.

In another embodiment, Z is 8-11 membered spiro heterobicyclyl or 8-10membered fused heterobicycloalkyl, wherein Z is substituted by 1, 2, 3or 4 R² groups.

In one embodiment, Z is:

or a stereoisomer thereof, wherein each X, X′, X², and X³ isindependently —CH₂—, —NH— or —O—, with the proviso that X² and X³ arenot —O— simultaneously; and wherein Z is substituted by 1, 2 or 3 R²groups.

In another embodiment, Z is:

or a stereoisomer thereof, and wherein Z is substituted by 1, 2 or 3 R²groups.

In one embodiment, Z¹ is H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl or 4-7membered heterocyclyl, wherein each of the C₁-C₆ alkyl, C₃-C₆ cycloalkyland 4-7 membered heterocyclyl is optionally independently substituted by1, 2 or 3 R^(2a) groups.

In one embodiment, R¹ is H, F, Cl, Br, I, N₃, CN, —NO₂, C₁-C₆ alkyl,C₁-C₆ alkoxyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 4-7membered heterocyclyl, —NR^(9a)R^(9b), —OR^(9c), —C(═O)OR^(9c),—C(═O)NR^(9a)R^(9b), or —S(═O)₂NR^(9a)R^(9b), wherein each of the C₁-C₆alkyl, C₁-C₆ alkoxyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and4-7 membered heterocyclyl is optionally independently substituted by 1,2 or 3 R¹¹ groups.

In another embodiment, each R² is independently F, Cl, Br, I, —NO₂, N₃,CN, —OH, —NH₂, —C(═O)CH₂CN, —NHC(═O)CH₂CN, —N(CH₃)C(═O)CH₂CN, C₁-C₆alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyl, C₃-C₆ cycloalkyl, 4-7 memberedheterocyclyl, phenyl, 5-6 membered heteroaryl, —NR^(10a)R^(10b),—O—(C₀-C₃ alkylene)-R^(10c), —O—(C₁-C₃ alkylene)-OR^(10c),—C(═O)R^(10d), —OC(═O)R^(10d), —N(R^(10e))C(═O)R^(10d),—C(═O)NR^(10a)R^(10b), —N(R^(10e))C(═O)NR^(10a)R^(10b),—C(═O)N(R^(10e))C(═O)R^(10d), —S(═O)₂R^(10f), —N(R^(10e))S(═O)₂R^(10f)or —S(═O)₂NR^(10a)R^(10b), or two adjacent R² taken together with theatoms to which they are attached form a C₃-C₆ cycloalkyl or 4-7 memberedheterocycloalkyl group, wherein each of the C₁-C₆ alkyl, C₂-C₆ alkenyl,C₁-C₆ alkoxyl, C₃-C₆ cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl group isoptionally independently substituted by 1, 2 or 3 R¹¹ groups;

In another embodiment, each R^(2a) is independently H, F, Cl, Br, I,—NO₂, N₃, CN, —OH, —NH₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyl,C₃-C₆ cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 memberedheteroaryl.

In one embodiment, R³ is H, C₃-C₆ hydroxyalkyl, C₃-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ aminoalkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, phenyl,4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein each ofthe C₃-C₆ hydroxyalkyl, C₃-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ aminoalkyl,C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, phenyl, 4-7 membered heterocyclyl and5-6 membered heteroaryl is optionally independently substituted by 1, 2or 3 R¹¹ groups.

In another embodiment, R³ is H, —CH₂C(CH₃)₂OH, —(CH₂)₂CH₂OH,—CH₂CH(OH)CH₃, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl,pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, pyrrolyl oroxazolyl, wherein each of the piperidinyl, pyrrolidinyl, morpholinyl,piperazinyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, pyrrolyl oroxazolyl is optionally independently substituted by 1, 2 or 3 R¹¹groups.

In one embodiment, R⁴ is C₁-C₆ hydroxyalkyl, C₃-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ aminoalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, phenyl, 4-7 membered heterocyclyl or 5-6 memberedheteroaryl, wherein R⁴ is optionally substituted by 1, 2, or 3 R¹¹groups.

In another embodiment, each of R⁵, R⁶, R⁷ and R⁸ is independently H,C₁-C₆ hydroxyalkyl, C₃-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ aminoalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 4-7 memberedheterocyclyl, phenyl or 5-6 membered heteroaryl, wherein each of theC₁-C₆ hydroxyalkyl, C₃-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ aminoalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 4-7 memberedheterocyclyl, phenyl and 5-6 membered heteroaryl is optionallyindependently substituted by 1, 2 or 3 R¹¹ groups.

In one embodiment, each R^(3a), R^(4a), R^(5a), R^(6a), R^(7a) andR^(8a) is independently H, F, Cl, CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆alkoxyl, C₁-C₆ alkylamino, —(C₀-C₃ alkylene)-(C₃-C₆ cycloalkyl), —(C₀-C₃alkylene)-(4-7 membered heterocyclyl), phenyl or 5-6 memberedheteroaryl, wherein each of the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆alkoxyl, C₁-C₆ alkylamino, —(C₀-C₃ alkylene)-(C₃-C₆ cycloalkyl), —(C₀-C₃alkylene)-(4-7 membered heterocyclyl), phenyl and 5-6 memberedheteroaryl is optionally independently substituted by 1, 2 or 3 R¹¹groups.

In another embodiment, each R^(9a), R^(9b), R^(9c), R^(10a), R^(10b),R^(10c) and R^(10e) is independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₃-C₆ cycloalkyl, —(C₀-C₃ alkylene)-(C₃-C₆cycloalkyl), —(C₀-C₃ alkylene)-(4-7 membered heterocyclyl), —(C₀-C₃alkylene)-phenyl, —(C₀-C₃ alkylene)-(5-6 membered heteroaryl), or R^(9a)and R^(9b), R^(10a) and R^(10b) taken together with the nitrogen atom towhich they are attached form a 4-7 membered heterocyclyl group, whereineach of the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl,C₃-C₆ cycloalkyl, —(C₀-C₃ alkylene)-(C₃-C₆ cycloalkyl), —(C₀-C₃alkylene)-(4-7 membered heterocyclyl), —(C₀-C₃ alkylene)-phenyl, —(C₀-C₃alkylene)-(5-6 membered heteroaryl), and 4-7 membered heterocyclyl groupis optionally substituted by 1, 2 or 3 substitutents independentlyselected from F, Cl, Br, CN, N₃, —NO₂, —OH, —NH₂, C₁-C₃ alkyl, C₁-C₃haloalkyl, C₁-C₃ alkoxy, C₁-C₃ hydroxyalkyl, C₁-C₃ aminoalkyl and C₁-C₃alkylamino.

In one embodiment, each R^(9a), R^(9b), R^(9c), R^(10a), R^(10b),R^(10c) and R^(10e) is independently H, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, allyl, vinyl,propenyl, C₁-C₄ alkoxyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl,-methylene-cyclopropy, -ethylidene-cyclopropyl, -methylene-cyclobutyl,-ethylidene-cyclobutyl, -methylene-cyclopentyl, -ethylidene-cyclopentyl,-methylene-cyclohexyl, -ethylidene-cyclohexyl, —(C₁-C₃ alkylene)-(4-7membered heterocyclyl), phenyl, pyridyl, pyridazinyl, pyrimidinyl,—(C₁-C₃ alkylene)-phenyl or —(C₁-C₃ alkylene)-(5-6 membered heteroaryl),wherein each of the methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, allyl, vinyl, propenyl, C₁-C₄ alkoxyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl,pyrrolidinyl, morpholinyl, piperazinyl, -methylene-cyclopropyl,-ethylidene-cyclopropyl, -methylene-cyclobutyl, -ethylidene-cyclobutyl,-methylene-cyclopentyl, -ethylidene-cyclopentyl, -methylene-cyclohexyl,-ethylidene-cyclohexyl, —(C₁-C₃ alkylene)-(4-7 membered heterocyclyl),phenyl, pyridyl, pyridazinyl, pyrimidinyl, —(C₁-C₃ alkylene)-phenyl and—(C₁-C₃ alkylene)-(5-6 membered heteroaryl) is optionally substituted by1, 2 or 3 substitutents independently selected from F, Cl, Br, CN, N₃,—NO₂, —OH, —NH₂, —CF₃, —OCH₃, —CH₂OH, —CH₂CH₂OH, —NHCH₃, —N(CH₃)₂ and—CH₂NH₂.

In another embodiment, each R^(10d) and R^(10f) is independently C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxyl, C₃-C₆ cycloalkyl,4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, —(C₁-C₃alkylene)-(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)-(4-7 memberedheterocyclyl), —(C₁-C₃ alkylene)-phenyl or —(C₁-C₃ alkylene)-(5-6membered heteroaryl), wherein each of the above substituents isoptionally substituted by 1, 2 or 3 substitutents independently selectedfrom F, Cl, Br, CN, N₃, —OH, —NH₂, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃alkoxy, C₁-C₃ hydroxyalkyl, C₁-C₃ aminoalkyl and C₁-C₃ alkylamino.

In one embodiment, each R^(10d) and R^(10f) is independently methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, vinyl,propenyl, phenyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl,C₁-C₄ alkoxyl, -methylene-cyclopropy, -ethylidene-cyclopropyl,-methylene-cyclobutyl, -ethylidene-cyclobutyl, -methylene-cyclopentyl,-ethylidene-cyclopentyl, -methylene-cyclohexyl or-ethylidene-cyclohexyl, wherein each of the above substituents isoptionally substituted by 1, 2 or 3 substitutents independently selectedfrom F, Cl, Br, CN, N₃, —OH, —NH₂, —CF₃, —OCH₃, —CH₂OH, —CH₂CH₂OH,—NHCH₃, —N(CH₃)₂ and —CH₂NH₂.

In one embodiment, each R¹¹ is independently F, Cl, Br, I, CN, —NO₂, N₃,—OH, —NH₂, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy,ethyoxyl, n-propoxy, isopropoxy, hydroxymethyl, hydroxyethyl,methylamino, dimethylamino or aminomethyl.

In another aspect, provided herein is a compound having Formula (II):

or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, apharmaceutically acceptable salt or a prodrug thereof, wherein each ofW, W₁, R¹², R¹³ and n is as defined herein.

In one embodiment, W is C₇-C₁₂ spiro bicycloalkyl, C₇-C₁₂ fusedbicycloalkyl, 7-12 membered spiro heterobicyclyl or 7-12 membered fusedheterobicycloalkyl, wherein W is substituted by 1, 2, 3, 4 or 5 R¹⁴groups;

W₁ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyl, C₁-C₆ aminoalkyl,C₁-C₆ hydroxyalkyl, C₃-C₆ cycloalkyl or 4-7 membered heterocyclyl;

R¹² is H, F, Cl, Br, I, N₃, CN, —NO₂, C₁-C₁₂ alkyl, C₁-C₁₂ alkoxyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, 3-12 memberedheterocyclyl, C₆-C₁₂ aryl, 5-12 membered heteroaryl, —NR^(15a)R^(15b),—OR^(15c), —C(═O)OR^(15c), —C(═O)NR^(15a)R^(15b) or—S(═O)₂NR^(15a)R^(15b), wherein each of the C₁-C₁₂ alkyl, C₁-C₁₂alkoxyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, 3-12membered heterocyclyl, C₆-C₁₂ aryl and 5-12 membered heteroaryl isoptionally independently substituted by 1, 2, 3, 4 or 5 R¹⁷ groups;

each R¹³ is independently H, F, Cl, CN, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl,C₁-C₁₂ alkoxyl, —(C₀-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₀-C₄alkylene)-(3-12 membered heterocyclyl), C₆-C₁₂ aryl or 5-12 memberedheteroaryl, wherein each of the C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₁-C₁₂alkoxyl, —(C₀-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₀-C₄ alkylene)-(3-12membered heterocyclyl), C₆-C₁₂ aryl and 5-12 membered heteroaryl isoptionally independently substituted by 1, 2, 3, 4 or 5 R¹⁷ groups;

each R¹⁴ is independently F, Cl, Br, I, NO₂, N₃, CN, C₃-C₁₂ alkyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂ hydroxyalkyl, C₃-C₁₂ alkoxyl,C₁-C₁₂ alkylamino, C₁-C₁₂ aminoalkyl, C₃-C₁₂ cycloalkyl, 4-7 memberedheterocyclyl, C₆-C₁₂ aryl, 6-cyanopyridazine-3-yl, —CH₂CN, —CH₂CH₂CN,—C(═O)R^(16d), —S(═O)₂R^(16e), —C(═O)NR^(16a)R^(16b),—S(═O)₂NR^(16a)R^(16b), —C(═O)O—R^(16c), —N(R^(16a))C(═O)R^(16f),—N(R^(16a))S(═O)₂R^(16g) or —OC(═O)R^(16f) wherein each of the —CH₂CN,—CH₂CH₂CN, C₃-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂hydroxyalkyl, C₃-C₁₂ alkoxyl, C₁-C₁₂ alkylamino, C₁-C₁₂ aminoalkyl,C₃-C₁₂ cycloalkyl, 4-7 membered heterocyclyl, C₆-C₁₂ aryl and6-cyanopyridazine-3-yl is optionally independently substituted by 1, 2,3, 4 or 5 R¹⁷ groups;

each R^(15a), R^(15b), R^(15c), R^(16a) and R^(16b) is independently H,C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, 3-12membered heterocyclyl, C₆-C₁₂ aryl, 5-12 membered heteroaryl, —(C₁-C₄alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄ alkylene)-(3-12 memberedheterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl), or —(C₁-C₄alkylene)-(5-12 membered heteroaryl), or R^(15a) and R^(15b), takentogether with the nitrogen atom to which they are attached form a 3-12membered heterocyclyl group, wherein each of the C₁-C₁₂ alkyl, C₂-C₁₂alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, 3-12 membered heterocyclyl,C₆-C₁₂ aryl, 5-12 membered heteroaryl, —(C₁-C₄ alkylene)-(C₃-C₁₂cycloalkyl), —(C₁-C₄ alkylene)-(3-12 membered heterocyclyl), —(C₁-C₄alkylene)-(C₆-C₁₂ aryl), and —(C₁-C₄ alkylene)-(5-12 memberedheteroaryl) is optionally substituted by 1, 2 or 3 substitutentsindependently selected from F, Cl, Br, CN, N₃, —NO₂, —OH, —NH₂, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ hydroxyalkyl, C₁-C₄aminoalkyl and C₁-C₄ alkylamino;

each R^(16d), R^(16e) and R^(16g) is independently C₂-C₁₂ alkyl, C₃-C₁₂cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryl, 5-12 memberedheteroaryl, —(C₁-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄alkylene)-(3-12 membered heterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl)or —(C₁-C₄ alkylene)-(5-12 membered heteroaryl), wherein each of theabove substituents is optionally substituted by 1, 2, 3 or 4substitutents independently selected from F, Cl, Br, CN, N₃, —OH, —NH₂,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ hydroxyalkyl, C₁-C₄aminoalkyl and C₁-C₄ alkylamino;

each R^(16c) and R^(16f) is independently C₁-C₃ alkyl, C₃-C₁₂cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryl, 5-12 memberedheteroaryl, —(C₁-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄alkylene)-(3-12 membered heterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl),or —(C₁-C₄ alkylene)-(5-12 membered heteroaryl), wherein each of theabove substituents is optionally substituted by 1, 2, 3 or 4substitutents independently selected from F, Cl, Br, CN, N₃, —OH, —NH₂,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ hydroxyalkyl, C₁-C₄aminoalkyl and C₁-C₄ alkylamino;

each R¹⁷ is independently F, Cl, Br, I, CN, NO₂, N₃, —OH, —NH₂, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,C₆-C₁₂ aryl, 4-7 membered heterocyclyl, 5-12 membered heteroaryl, C₁-C₆aminoalkyl, C₁-C₆ alkylamino, C₁-C₆ alkoxyl, C₁-C₆ hydroxyalkyl,—NH(C₀-C₄ alkylene)-(C₃-C₆ cycloalkyl), —NH(C₀-C₄ alkylene)-(4-7membered heterocyclyl), —N[(C₀-C₄ alkylene)-(C₃-C₆ cycloalkyl)]₂,—N[(C₀-C₄ alkylene)-(4-7 membered heterocyclyl)]₂, —O(C₀-C₄alkylene)-(C₃-C₆ cycloalkyl) or —O(C₀-C₄ alkylene)-(4-7 memberedheterocyclyl); and

n is 0, 1 or 2.

In another embodiment, W is 8-11 membered spiro heterobicyclyl or 8-10membered fused heterobicycloalkyl, wherein W is substituted by 1, 2, 3or 4 R¹⁴ groups.

In one embodiment, W is:

or a stereoisomer thereof, wherein each Y, Y′, Y² and Y³ isindependently —CH₂—, —NH— or —O—, with the proviso that Y² and Y³ arenot —O— simultaneously; and wherein W is substituted by 1, 2 or 3 R¹⁴groups.

In another embodiment, W is:

or a stereoisomer thereof, and wherein W is substituted by 1, 2 or 3 R¹⁴groups.

In one embodiment, W₁ is H, methyl, ethyl, n-propyl, isopropyl orcyclopropyl.

In another embodiment, R¹² is H, F, Cl, Br, I, N₃, CN, —NO₂, C₁-C₄alkyl, C₁-C₄ alkoxyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl,4-7 membered heterocyclyl, —NR^(15a)R^(15b), —OR^(15c), —C(═O)OR^(15c),—C(═O)NR^(15a)R^(15b) or —S(═O)₂NR^(15a)R^(15b), wherein each of theC₁-C₄ alkyl, C₁-C₄ alkoxyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl and 4-7 membered heterocyclyl is optionally independentlysubstituted by 1, 2 or 3 R¹⁷ groups.

In one embodiment, each R¹³ is independently H, F, Cl, CN, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₁-C₄ alkoxyl, —(C₀-C₃ alkylene)-(C₃-C₆ cycloalkyl) or—(C₀-C₃ alkylene)-(4-7 membered heterocyclyl), wherein each of the C₁-C₄alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxyl, —(C₀-C₃ alkylene)-(C₃-C₆cycloalkyl) and —(C₀-C₃ alkylene)-(4-7 membered heterocyclyl) isoptionally independently substituted by 1, 2 or 3 R¹⁷ groups.

In another embodiment, each R¹⁴ is independently F, Cl, Br, I, —NO₂, N₃,CN, C₃-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ hydroxyalkyl, C₃-C₆alkoxyl, C₁-C₆ alkylamino, C₁-C₆ aminoalkyl, C₃-C₆ cycloalkyl, 4-7membered heterocyclyl, phenyl, 6-cyanopyridazine-3-yl, —CH₂CN,—CH₂CH₂CN, —C(═O)R^(16d), —S(═O)₂R^(16e), —C(═O)NR^(16a)R^(16b),—S(═O)₂NR^(16a)R^(16b), —C(═O)O—R^(16c),—N(R^(16a))C(═O)R^(16f)—N(R^(16a))S(═O)₂R^(16g) or —OC(═O)R^(16f)wherein each of the —CH₂CN, —CH₂CH₂CN, C₃-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ hydroxyalkyl, C₃-C₆ alkoxyl, C₁-C₆ alkylamino, C₁-C₆aminoalkyl, C₃-C₆ cycloalkyl, 4-7 membered heterocyclyl, phenyl and6-cyanopyridazine-3-yl is optionally independently substituted by 1, 2or 3 R¹⁷ groups.

In one embodiment, each R¹⁴ is independently F, Cl, Br, —NO₂, CN,

In another embodiment, each R^(15a), R^(15b), R^(15c), R^(16a) andR^(16b) is independently H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,C₃-C₆ cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 memberedheteroaryl, —(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)-(4-7membered heterocyclyl), —(C₁-C₃ alkylene)-phenyl or —(C₁-C₃alkylene)-(5-6 membered heteroaryl), or R^(15a) and R^(15b), takentogether with the nitrogen atom to which they are attached form a 4-7membered heterocyclyl group, wherein each of the C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, 4-7 membered heterocyclyl,phenyl, 5-6 membered heteroaryl, —(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl),—(C₁-C₃ alkylene)-(4-7 membered heterocyclyl), —(C₁-C₃ alkylene)-phenyland —(C₁-C₃ alkylene)-(5-6 membered heteroaryl) is optionallysubstituted by 1, 2 or 3 substitutents independently selected from F,Cl, Br, CN, N₃, —NO₂, —OH, —NH₂, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃alkoxy, C₁-C₃ hydroxyalkyl, C₁-C₃ aminoalkyl and C₁-C₃ alkylamino.

In another embodiment, each R^(16d), R^(16e) and R^(16g) isindependently C₂-C₆ alkyl, C₃-C₆ cycloalkyl, 4-7 membered heterocyclyl,phenyl, 5-6 membered heteroaryl, —(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl),—(C₁-C₃ alkylene)-(4-7 membered heterocyclyl), —(C₁-C₃ alkylene)-phenyl,or —(C₁-C₃ alkylene)-(5-6 membered heteroaryl), wherein each of theabove substituents is optionally substituted by 1, 2, 3 or 4substitutents independently selected from F, Cl, Br, CN, N₃, —OH, —NH₂,C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃ hydroxyalkyl, C₁-C₃aminoalkyl and C₁-C₃ alkylamino.

In one embodiment, each R^(16c) and R^(16f) is independently C₁-C₃alkyl, C₃-C₆ cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 memberedheteroaryl, —(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)-(4-7membered heterocyclyl), —(C₁-C₃ alkylene)-phenyl, or —(C₁-C₃alkylene)-(5-6 membered heteroaryl), wherein each of the abovesubstituents is optionally substituted by 1, 2, 3 or 4 substitutentsindependently selected from F, Cl, Br, CN, N₃, —OH, —NH₂, C₁-C₃ alkyl,C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃ hydroxyalkyl, C₁-C₃ aminoalkyl andC₁-C₃ alkylamino.

In another aspect, provided herein is a pharmaceutical compositioncomprising the compound disclosed herein, and a pharmaceuticallyacceptable excipient, carrier, adjuvant, vehicle or a combinationthereof.

In one embodiment, the pharmaceutical composition disclosed hereinfurther comprising a therapeutic agent selected from the groupconsisting of chemotherapeutic agents, anti-proliferative agents,phosphodiesterase 4 (PDE4) inhibitors, β₂-adrenoreceptor agonists,corticosteroids, non-steroidal GR agonists, anticholinergic agents,antihistamine, anti-inflammatory agents, immunosuppressants,immunomodulators, agents for treating atherosclerosis, agents fortreating pulmonary fibrosis and combinations thereof.

In another aspect, provided herein is a method of preventing, managing,treating or lessening the severity of a protein kinase-mediated diseasein a patient by administering to the patient with the compound disclosedherein or the pharmaceutical composition disclosed herein.

In one embodiment, the protein kinase-mediated disease is JAK-mediateddisease, a FLT3-mediated disease, an Aurora-mediated disease.

In another embodiment, the protein kinase-mediated disease is aproliferative disease, an autoimmune disease, an allergic disease, aninflammatory disease or a transplantation rejection.

In another embodiment, the protein kinase-mediated disease is a cancer,polycythemia vera, essential thrombocytosis, myelofibrosis, chronicmyelogenous leukemia (CML), acute myeloid leukemia (AML), acutelymphocytic leukemia (ALL), chronic obstruction pulmonary disease(COPD), asthma, systemic lupus erythematosis, cutaneous lupuserythematosis, lupus nephritis, dermatomyositis, Sjogren's syndrome,psoriasis, type I diabetes mellitus, an allergic airway disease,sinusitis, eczema, hives, a food allergy, an allergies to insect venom,inflammatory bowel syndrome, Chron's disease, rheumatoid arthritis,juvenile arthritis, psoriatic arthritis, an organ transplant rejection,a tissue transplant rejection or a cell transplant rejection.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in preventing, managing, treatingor lessening the severity of a protein kinase-mediated disease in apatient.

In another aspect, provided herein is the use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for preventing, treating, or lessening a proteinkinase-mediated disease.

In another aspect, provided herein is a method of modulating theactivity of a protein kinase with the compound or the pharmaceuticalcomposition disclosed herein.

In one embodiment, the protein kinase is JAK kinases, FLT3 kinase,Aurora kinases or a combination thereof. In one embodiment, JAK kinasesare JAK1, JAK2, JAK3 or TYK2. In one embodiment, Aurora kinases areAurora-A, Aurora-B, or Aurora-C.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in modulating the activity of aprotein kinase.

In still another aspect, provided herein is use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for modulating the activity of a protein kinase.

In another aspect, provided herein are methods for preparation,separation and purification of the compounds represented by Formula (I)and Formula (II).

Biological test results indicate that the compounds provided herein canbe used as preferable inhibitors of protein kinases.

Any embodiment disclosed herein can be combined with other embodimentsas long as they are not contradictory to one another, even though theembodiments are described under different aspects of the invention. Inaddition, any technical feature in one embodiment can be applied to thecorresponding technical feature in other embodiment as long as they arenot contradictory to one another, even though the embodiments aredescribed under different aspects of the invention.

The foregoing merely summarizes certain aspects of the invention and isnot intended to be limiting in nature. These aspects and other aspectsand embodiments are described more fully below.

DETAILED DESCRIPTION OF THE INVENTION

Definitions and General Terminology

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. The invention is intended to cover allalternatives, modifications, and equivalents which may be includedwithin the scope of the present invention as defined by the claims. Oneskilled in the art will recognize many methods and materials similar orequivalent to those described herein, which could be used in thepractice of the present invention. The present invention is in no waylimited to the methods and materials described herein. In the event thatone or more of the incorporated literature, patents, and similarmaterials differs from or contradicts this application, including butnot limited to defined terms, term usage, described techniques, or thelike, this application controls.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one skilled in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference in their entirety.

As used herein, the following definitions shall apply unless otherwiseindicated. For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, and the Handbook of Chemistry and Physics, 75^(th) Ed. 1994.Additionally, general principles of organic chemistry are described inSorrell et al., “Organic Chemistry”, University Science Books,Sausalito: 1999, and Smith et al., “March's Advanced Organic Chemistry”,John Wiley & Sons, New York: 2007, all of which are incorporated byreference in their entireties.

The grammatical articles “a”, “an” and “the”, as used herein, areintended to include “at least one” or “one or more” unless otherwiseindicated herein or clearly contradicted by the context. Thus, thearticles are used herein to refer to one or more than one (i.e. at leastone) of the grammatical objects of the article. By way of example, “acomponent” means one or more components, and thus, possibly, more thanone component is contemplated and may be employed or used in animplementation of the described embodiments.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like. In certain embodiments,the subject is a primate. In yet other embodiments, the subject is ahuman.

As used herein, “patient” refers to a human (including adults andchildren) or other animal. In one embodiment, “patient” refers to ahuman.

The term “comprising” is meant to be open ended, including the indicatedcomponent but not excluding other elements.

“Stereoisomers” refers to compounds which have identical chemicalconstitution, but differ with regard to the arrangement of the atoms orgroups in space. Stereoisomers include enantiomer, diastereomers,conformer (rotamer), geometric (cis/trans) isomer, atropisomer, etc.

“Chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties or biological activities. Mixture ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography such as HPLC.

Stereochemical definitions and conventions used herein generally followParker et al., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York and Eliel et al., “Stereochemistry ofOrganic Compounds”, John Wiley & Sons, Inc., New York, 1994.

Many organic compounds exist in optically active forms, i.e., they havethe ability to rotate the plane of plane-polarized light. In describingan optically active compound, the prefixes D and L, or R and S, are usedto denote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and 1 or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or 1 meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. A specific stereoisomer may be referred toas an enantiomer, and a mixture of such stereoisomers is called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.

Any asymmetric atom (e.g., carbon or the like) of the compound(s)disclosed herein can be present in racemic or enantiomerically enriched,for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration.

Depending on the choice of the starting materials and procedures, thecompounds can be present in the form of one of the possiblestereoisomers or as mixtures thereof, such as racemates anddiastereoisomer mixtures, depending on the number of asymmetric carbonatoms. Optically active (R)- and (S)-isomers may be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques. If the compound contains a double bond, the substituent maybe E or Z configuration. If the compound contains a disubstitutedcycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration.

Any resulting mixtures of stereoisomers can be separated on the basis ofthe physicochemical differences of the constituents, into the pure orsubstantially pure geometric isomers, enantiomers, diastereomers, forexample, by chromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by methods known to those skilled inthe art, e.g., by separation of the diastereomeric salts thereof.Racemic products can also be resolved by chiral chromatography, e.g.,high performance liquid chromatography (HPLC) using a chiral adsorbent.Preferred enantiomers can also be prepared by asymmetric syntheses. See,for example, Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis(2^(nd) Ed. Robert et al., Elsevier, Oxford, U K, 2012); Eliel et al.,Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilenet al., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L.Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972). ChiralSeparation Techniques: A Practical Approach (Subramanian, G. Ed.,Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.Where tautomerization is possible (e.g. in solution), a chemicalequilibrium of tautomers can be reached. For example, proton tautomers(also known as prototropic tautomers) include interconversions viamigration of a proton, such as keto-enol and imine-enamineisomerizations. Valence tautomers include interconversions byreorganization of some of the bonding electrons. A specific example ofketo-enol tautomerization is the interconversion of pentane-2,4-dioneand 4-hydroxypent-3-en-2-one tautomers. Another example oftautomerization is phenol-keto tautomerization. A specific example ofphenol-keto tautomerization is the interconversion of pyridin-4-ol andpyridin-4(1H)-one tautomers. Unless otherwise stated, all tautomericforms of the compounds disclosed herein are within the scope of theinvention.

As described herein, compounds disclosed herein may optionally besubstituted with one or more substituents, such as those illustratedbelow, or as exemplified by particular classes, subclasses, and speciesof the invention. It will be appreciated that the phrase “optionallysubstituted” is used interchangeably with the phrase “substituted orunsubstituted”. The term “optional” or “optionally” means that thesubsequently described event or circumstance may but need not occur, andthat the description includes instances where the event or circumstanceoccurs and instances in which it does not. In general, the term“substituted” refers to the replacement of one or more hydrogen radicalsin a given structure with the radical of a specified substituent. Unlessotherwise indicated, an optionally substituted group may have asubstituent at each substitutable position of the group. When more thanone position in a given structure can be substituted with more than onesubstituent selected from a specified group, the substituent may beeither the same or different at each position.

Some non-limiting examples of the substituents include D, F, Cl, Br, I,CN, N₃, —CN, —NO₂, —OH, —SH, —NH₂, —C(═O)CH₂CN, —NHC(═O)CH₂CN,—N(CH₃)C(═O)CH₂CN, —NR^(10a)R^(10b), —C(═O)R^(10d), —OC(═O)R^(10d),—C(═O)OR^(10c), —N(R^(10e))C(═O)R^(10d), —C(═O)NR^(10a)R^(10b),—N(R^(10e))C(═O)NR^(10a)R^(10b), —C(═O)N(R^(10e))C(═O)R^(10d),—S(═O)₂R^(10f), —N(R^(10e))S(═O)₂R^(10f), S(═O)₂NR^(10a)R^(10b), alkyl,haloalkyl, alkenyl, alkynyl, alkoxyl, hydroxyalkyl, alkylthiolyl,alkylamino, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,and the like, wherein each R^(10a), R^(10b), R^(10c), R^(10d), R^(10e)and R^(10f) carry the definitions described herein.

At various places in the present specification, substituents ofcompounds disclosed herein are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁-C₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

At various places in the present specification, linking substituents aredescribed. Where the structure clearly requires a linking group, theMarkush variables listed for that group are understood to be linkinggroups. For example, if the structure requires a linking group and theMarkush group definition for that variable lists “alkyl” or “aryl” thenit is understood that the “alkyl” or “aryl” represents a linkingalkylene group or arylene group, respectively.

The term “alkyl” or “alkyl group” refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of 1 to 20 carbon atoms,wherein the alkyl radical may be optionally substituted independentlywith one or more substituents described below. Unless otherwisespecified, the alkyl group contains 1-20 carbon atoms. In oneembodiment, the alkyl group contains 1-12 carbon atoms. In anotherembodiment, the alkyl group contains 1-6 carbon atoms. In anotherembodiment, the alkyl group contains 3-6 carbon atoms. In still anotherembodiment, the alkyl group contains 1-4 carbon atoms. In yet anotherembodiment, the alkyl group contains 1-3 carbon atoms. The alkyl radicalmay be optionally substituted independently with one or moresubstituents described herein.

Some non-limiting examples of the alkyl group include methyl (Me, —CH₃),ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl(i-Pr, isopropyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃),2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH(CH₃)CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl, 1-octyl, and the like.

The term “alkylene” refers to a saturated divalent or multivalenthydrocarbon group derived from a straight or branched chain saturatedhydrocarbon by the removal of two or more hydrogen atoms. Unlessotherwise specified, the alkylene group contains 1-12 carbon atoms. Inone embodiment, the alkylene group contains 1-6 carbon atoms. In anotherembodiment, the alkylene group contains 1-4 carbon atoms. In anotherembodiment, the alkylene group contains 0-4 carbon atoms. In anotherembodiment, the alkylene group contains 0-3 carbon atoms. In stillanother embodiment, the alkylene group contains 1-3 carbon atoms. Thealkylene group contains 0 carbon atom refers to a single bond. Thealkylene group is exemplified by methylene (—CH₂—), ethylidene(—CH₂CH₂—), isopropylidene (—CH(CH₃)CH₂—), and the like.

The term “alkenyl” refers to a linear or branched-chain monovalenthydrocarbon radical of 2 to 12 carbon atoms with at least one site ofunsaturation, i.e., a carbon-carbon, sp² double bond, wherein thealkenyl radical may be optionally substituted independently with one ormore substituents described herein, and includes radicals having “cis”and “trans” orientations, or alternatively, “E” and “Z” orientations. Inone embodiment, the alkenyl group contains 2-8 carbon atoms. In anotherembodiment, the alkenyl group contains 2-6 carbon atoms. In stillanother embodiment, the alkenyl group contains 2-4 carbon atoms. Somenon-limiting examples of the alkenyl group include ethylenyl or vinyl(—CH═CH₂), allyl (—CH₂CH═CH₂), and the like. The alkenyl radical may beoptionally substituted independently with one or more substituentsdescribed herein.

The term “alkynyl” refers to a linear or branched-chain monovalenthydrocarbon radical of 2 to 12 carbon atoms with at least one site ofunsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynylradical may be optionally substituted independently with one or moresubstituents described herein. In one embodiment, the alkynyl groupcontains 2-8 carbon atoms. In another embodiment, the alkynyl groupcontains 2-6 carbon atoms. In still another embodiment, the alkynylgroup contains 2-4 carbon atoms. Some non-limiting examples of thealkynyl group include ethynyl (—C≡CH), propargyl (—CH₂C≡CH), propynyl(—C═C—CH₃), and the like.

The term “alkoxy” refers to an alkyl group, as previously defined,attached to the principal carbon atom through an oxygen atom. Unlessotherwise specified, the alkoxy group contains 1-12 carbon atoms. In oneembodiment, the alkoxy group contains 1-6 carbon atoms. In anotherembodiment, the alkoxy group contains 1-4 carbon atoms. In still anotherembodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxyradical may be optionally substituted independently with one or moresubstituents described herein.

Some non-limiting examples of alkoxy groups include methoxy (MeO,—OCH₃), ethoxy (EtO, —OCH₂CH₃), 1-propoxy (n-PrO, n-propoxy,—OCH₂CH₂CH₃), 2-propoxy (i-PrO, isopropoxy, —OCH(CH₃)₂), 1-butoxy(n-BuO, n-butoxy, —OCH₂CH₂CH₂CH₃), 2-methyl-1-propoxy (i-BuO, i-butoxy,—OCH₂CH(CH₃)₂), 2-butoxy (s-BuO, s-butoxy, OCH(CH₃)CH₂CH₃),2-methyl-2-propoxy (t-BuO, t-butoxy, —OC(CH₃)₃), 1-pentoxy (n-pentoxy,—OCH₂CH₂CH₂CH₂CH₃), 2-pentoxy (—OCH(CH₃)CH₂CH₂CH₃), 3-pentoxy(—OCH(CH₂CH₃)₂), 2-methyl-2-butoxy (—OC(CH₃)₂CH₂CH₃), 3-methyl-2-butoxy(—OCH(CH₃)CH(CH₃)₂), 3-methyl-1-butoxy (—OCH₂CH₂CH(CH₃)₂),2-methyl-1-butoxy (—OCH₂CH(CH₃)CH₂CH₃), and the like.

The term “haloalkyl”, “haloalkenyl” or “haloalkoxy” refers to alkyl,alkenyl, or alkoxy, as the case may be, substituted with one or morehalogen atoms. Some non-limiting examples of haloalkyl and haloalkoxyare include trifluoromethyl (—CF₃), trifluoromethoxy (—OCF₃),difluoroethyl (—CH₂CHF₂, —CF₂CH₃, —CHFCH₂F), trifluoroethyl (—CH₂CF₃,—CF₂CH₂F, —CFHCHF₂) and the like.

The term “hydroxyalkyl” and “hydroxyalkoxy” refers to alkyl or alkoxy,as the case may be, substituted with one or more hydroxy. Somenon-limiting examples of hydroxyalkyl and hydroxyalkoxy includehydroxymethyl (—CH₂OH), hydroxyethyl (—CH₂CH₂OH, —CH(OH)CH₃),hydroxymethoxy (—OCH₂OH) and the like.

The term “carbocycle”, “carbocyclyl” or “carbocyclic ring” refers to amonovalent or multivalent non-aromatic, saturated or partiallyunsaturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclicor tricyclic ring system. The carbobicyclyl refers to a spirocarbobicyclyl, a fused carbobicyclyl or a bridged carbobicyclyl. Somenon-limiting examples of carbocyclyl groups include cycloalkyl,cycloalkenyl, and cycloalkynyl. Further non-limiting examples ofcarbocyclyl group include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, l-cyclohex-3-enyl,cyclohexadienyl, and the like.

The term “cycloalkyl” refers to a monovalent or multivalent saturatedring having 3 to 12 carbon atoms as a monocyclic, bicyclic, or tricyclicring system. The bicycloalkyl refers to spiro bicycloalkyl, fusedbicycloalkyl or bridged bicycloalkyl. In one embodiment, the cycloalkylcontains 3-12 carbon atoms. In another embodiment, the cycloalkylcontains 3-8 carbon atoms. In another embodiment, the cycloalkylcontains 3-6 carbon atoms. In another embodiment, the cycloalkyl refersto a C₇-C₁₂ bicycloalkyl which contains 7-12 carbon atoms. The C₇-C₁₂bicycloalkyl includes C₇-C₁₂ spiro, C₇-C₁₂ fused bicycloalkyl and C₇-C₁₂bridged bicycloalkyl. In yet another embodiment, cycloalkyl may be aC₈-C₁₁ bicycloalkyl which refers to C₈-C₁₁ spiro, C₈-C₁₁ fusedbicycloalkyl and C₈-C₁₁ bridged bicycloalkyl. Some non-limiting examplesof cycloalkyl, include the C₃-C₆ cycloalkyl which refers to cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl radical may beoptionally substituted independently with one or more substituentsdescribed herein.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic ring” as usedinterchangeably herein refers to a monovalent or multivalent, saturatedor partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclicring containing 3-12 ring atoms of which at least one ring atom isselected from nitrogen, sulfur and oxygen, and which may, unlessotherwise specified, be carbon or nitrogen linked, and of which a —CH₂—group can optionally be replaced by a —C(═O)— group. Ring sulfur atomsmay be optionally oxidized to form S-oxides. Ring nitrogen atoms maybeoptionally oxidized to form N-oxides. The heterocyclyl containssaturated heterocyclyl (i.e. heterocycloalkyl) and partially unsaturatedheterocyclyl. Some non-limiting examples of heterocyclyl includeoxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 1-pyrrolinyl,2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,dihydrothienyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl,dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl,thioxanyl, dithianyl, homopiperazinyl, homopiperidinyl, oxepanyl,thiepanyl, oxazepinyl (e.g. 1,4-oxazepinyl, 1,2-oxazepinyl), diazepinyl(e.g. 1,4-diazepinyl, 1,2-diazepinyl), dioxpinyl (e.g. 1,4-dioxpinyl,1,2-dioxpinyl), thiazepinyl (e.g. 1,4-thiazepinyl, 1,2-thiazepinyl),2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 2-azaspiro[4.4]nonanyl,1,6-dioxaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl,8-azaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl,3-azaspiro[5.5]undecanyl, 2-azaspiro[5.5]undecanyl,octahydro-1H-isoindolyl, octahydrocyclopenta[c]pyrrolyl, indolinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxolyl,hexahydrofuro[3,2-b]furanyl, decahydroisoquinolinyl, and the like. Somenon-limiting examples of heterocyclyl wherein —CH₂— group is replaced by—C(═O)— moiety are 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl,2-piperidinonyl and 3,5-dioxopiperidinyl. Some non-limiting examples ofheterocyclyl wherein the ring sulfur atom is oxidized are sulfolanyl,1,1-dioxotetrahydrothiophenyl, 1,1-dioxothiomorpholinyl,1,1-dioxotetrahydro-2H-thiopyranyl. The heterocyclyl group may beoptionally substituted with one or more substituents described herein.

In one embodiment, heterocyclyl may be a 3-8 membered heterocyclyl,which refers to a monovalent or multivalent, saturated or partiallyunsaturated, monocyclic ring containing 3-8 ring atoms, of which atleast one ring atom is selected from nitrogen, sulfur and oxygen, and ofwhich may, unless otherwise specified, be carbon or nitrogen linked, andof which a —CH₂— group can optionally be replaced by a —C(═O)— group.Ring sulfur atoms may be optionally oxidized to form S-oxides. Ringnitrogen atoms maybe optionally oxidized to form N-oxides. Somenon-limiting examples of 3-8 membered heterocyclyl include azetidinyl,oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl,pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl,1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl,2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, dioxanyl, thioxanyl, dithianyl,homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, and the like. Some non-limiting examples ofheterocyclyl wherein —CH₂— group is replaced by —C(═O)— moiety are2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl and3,5-dioxopiperidinyl. Some non-limiting examples of heterocyclyl whereinthe ring sulfur atom is oxidized are sulfolanyl,1,1-dioxothiomorpholinyl, and the like. The 3-8 membered heterocyclylgroup may be optionally substituted with one or more substituentsdescribed herein.

In another embodiment, heterocyclyl may be a 4-7 membered heterocyclyl,which refers to a monovalent or multivalent, saturated or partiallyunsaturated, non-aromatic monocyclic ring containing 4-7 ring atoms, ofwhich at least one ring atom is selected from nitrogen, sulfur andoxygen, and of which may, unless otherwise specified, be carbon ornitrogen linked, and of which a —CH₂— group can optionally be replacedby a —C(═O)— group. Ring sulfur atoms may be optionally oxidized to formS-oxides. Ring nitrogen atoms maybe optionally oxidized to formN-oxides. Some non-limiting examples of 4-7 membered heterocyclylinclude azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl,3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl,1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl,2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, dioxanyl, thioxanyl, dithianyl,homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl and thiazepinyl. The 4-7 membered heterocyclyl group may beoptionally substituted with one or more substituents described herein.

In another embodiment, heterocyclyl refers to a 7-12 memberedheterocyclyl, which refers to a monovalent or multivalent, saturated orpartially unsaturated spiro, fused or bridged heterobicyclyl ringcontaining 7-12 ring atoms, of which at least one ring atom is selectedfrom nitrogen, sulfur and oxygen, and which may, unless otherwisespecified, be carbon or nitrogen linked, and of which a —CH₂— group canoptionally be replaced by a —C(═O)— group. Ring sulfur atoms may beoptionally oxidized to form S-oxides. Ring nitrogen atoms maybeoptionally oxidized to form N-oxides. Some non-limiting examples of 7-12membered heterocyclyl include indolinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxolyl,2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 2-azaspiro[4.4]nonanyl (e.g.2-azaspiro[4.4]nonane-4-yl, 2-azaspiro[4.4]nonane-2-yl),1,6-dioxaspiro[4.4]nonanyl (e.g. 1,6-dioxaspiro[4.4]nonan-9-yl,1,6-dioxaspiro[4.4]nonane-4-yl), 2-azaspiro[4.5]decanyl (e.g.2-azaspiro[4.5]decane-8-yl, 2-azaspiro[4.5]decane-2-yl),7-azaspiro[4.5]decanyl (e.g. 7-azaspiro[4.5]decane-8-yl,7-azaspiro[4.5]decane-2-yl), 3-azaspiro[5.5]undecanyl (e.g.3-azaspiro[5.5]undecane-3-yl, 3-azaspiro[5.5]undecane-9-yl),2-azaspiro[5.5]undecanyl, 8-azaspiro[4.5]decanyl,decahydroisoquinolinyl, octahydro-1H-isoindolyl (e.g.octahydro-1H-isoindole-5-yl, octahydro-1H-isoindole-7-yl),octahydrocyclopenta[c]pyrrolyl (e.g. octahydrocyclopenta[c]pyrrole-5-yl,octahydrocyclopenta[c]pyrrole-2-yl), hexahydrofuro[3,2-b]furanyl (e.g.hexahydrofuro[3,2-b]furan-2-yl, hexahydrofuro[3,2-b]furan-3-yl), and thelike. The 7-12 membered heterocyclyl group may be optionally substitutedwith one or more substituents described herein.

In still one embodiment, heterocyclyl refers to a 7-12 membered spiroheterobicyclyl, which refers to a monovalent or multivalent, saturatedor partially unsaturated, non-aromatic, spiro heterobicyclyl ringcontaining 7-12 ring atoms, of which at least one ring atom is selectedfrom nitrogen, sulfur and oxygen, and which may, unless otherwisespecified, be carbon or nitrogen linked, and of which a —CH₂— group canoptionally be replaced by a —C(═O)— group. Ring sulfur atoms may beoptionally oxidized to form S-oxides. Ring nitrogen atoms maybeoptionally oxidized to form N-oxides. The 7-12 membered spiroheterobicyclyl contains 7-12 membered saturated spiro heterobicyclyl(i.e. 7-12 membered spiro heterobicycloalkyl) and 7-12 memberedpartially unsaturated spiro heterobicyclyl. Some non-limiting examplesof 7-12 membered spiro heterobicyclyl include 2-azaspiro[4.4]nonanyl(e.g. 2-azaspiro[4.4]nonane-4-yl, 2-azaspiro[4.4]nonane-2-yl),1,6-dioxaspiro[4.4]nonanyl (e.g. 1,6-dioxaspiro[4.4]nonan-9-yl,1,6-dioxaspiro[4.4]nonane-4-yl), 2-azaspiro[4.5]decanyl (e.g.2-azaspiro[4.5]decane-8-yl, 2-azaspiro[4.5]decane-2-yl),7-azaspiro[4.5]decanyl (e.g. 7-azaspiro[4.5]decane-8-yl,7-azaspiro[4.5]decane-2-yl), 3-azaspiro[5.5]undecanyl (e.g.3-azaspiro[5.5]undecane-3-yl, 3-azaspiro[5.5]undecane-9-yl),2-azaspiro[5.5]undecanyl, 8-azaspiro[4.5]decanyl, and the like. The 7-12membered spiro heterobicyclyl group may be optionally substituted withone or more substituents described herein.

In still another embodiment, heterocyclyl refers to a 8-11 memberedspiro heterobicyclyl, which refers to a monovalent or multivalent,saturated or partially unsaturated, non-aromatic, spiro heterobicyclylring containing 8-11 ring atoms, of which at least one ring atom isselected from nitrogen, sulfur and oxygen, and which may, unlessotherwise specified, be carbon or nitrogen linked, and of which a —CH₂—group can optionally be replaced by a —C(═O)— group. Ring sulfur atomsmay be optionally oxidized to form S-oxides. Ring nitrogen atoms maybeoptionally oxidized to form N-oxides. The 8-11 membered spiroheterobicyclyl contains 8-11 membered saturated spiro heterobicyclyl(i.e. 8-11 membered spiro heterobicycloalkyl) and 8-11 memberedpartially unsaturated spiro heterobicyclyl. Some non-limiting examplesof 8-11 membered spiro heterobicyclyl include 2-azaspiro[4.4]nonanyl(e.g. 2-azaspiro[4.4]nonane-4-yl, 2-azaspiro[4.4]nonane-2-yl),1,6-dioxaspiro[4.4]nonanyl (e.g. 1,6-dioxaspiro[4.4]nonan-9-yl,1,6-dioxaspiro[4.4]nonane-4-yl), 2-azaspiro[4.5]decanyl (e.g.2-azaspiro[4.5]decane-8-yl, 2-azaspiro[4.5]decane-2-yl),7-azaspiro[4.5]decanyl (e.g. 7-azaspiro[4.5]decane-8-yl,7-azaspiro[4.5]decane-2-yl), 3-azaspiro[5.5]undecanyl (e.g.3-azaspiro[5.5]undecane-3-yl, 3-azaspiro[5.5]undecane-9-yl),2-azaspiro[5.5]undecanyl, 8-azaspiro[4.5]decanyl, and the like. The 8-11membered spiro heterobicyclyl group may be optionally substituted withone or more substituents described herein.

In yet another embodiment, heterocyclyl refers to a 7-12 membered fusedheterobicyclyl, which refers to a monovalent or multivalent, saturatedor partially unsaturated, non-aromatic fused heterobicyclyl ringcontaining 7-12 ring atoms, of which at least one ring atom is selectedfrom nitrogen, sulfur and oxygen, and which may, unless otherwisespecified, be carbon or nitrogen linked, and of which a —CH₂— group canoptionally be replaced by a —C(═O)— group. Ring sulfur atoms may beoptionally oxidized to form S-oxides. Ring nitrogen atoms maybeoptionally oxidized to form N-oxides. The 7-12 membered fusedheterobicyclyl contains 7-12 membered saturated fused heterobicyclyl(i.e. 7-12 membered fused heterobicycloalkyl) and 7-12 memberedpartially unsaturated fused heterobicyclyl. Some non-limiting examplesof 7-12 membered fused heterobicyclyl includeoctahydrocyclopenta[c]pyrrolyl, octahydro-1H-isoindolyl, indolinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxolyl,hexahydrofuro[3,2-b]furanyl, hexahydrofuro[2,3-b]furanyl,decahydroisoquinolinyl, and the like. The 7-12 membered fusedheterobicyclyl group may be optionally substituted with one or moresubstituents described herein.

The terms “bridged bicyclic ring”, “bridged cyclic”, “bridged bicyclyl”and “bridged cyclyl” are used interchangeably refer to a monovalent ormultivalent saturated or partially unsaturated, but not aromaticbicyclic ring system, and such that two rings share two atoms and two ormore common single bond. Such a system may contain isolated orconjugated unsaturation, but not aromatic or heteroaromatic rings in itscore structure (but may have aromatic substitution thereon).

The terms “fused bicyclic ring”, “fused cyclic”, “fused bicyclyl” and“fused cyclyl” are used interchangeably refer to a monovalent ormultivalent saturated or partially unsaturated, but not aromaticbicyclic ring system, and such that two rings share one common bond.Such a system may contain isolated or conjugated unsaturation, but notaromatic or heteroaromatic rings in its core structure (but may havearomatic substitution thereon).

The terms “spirocyclyl”, “spirocyclic”, “spiro bicyclyl” and “spirobicyclic” are used interchangeably and refer to a monovalent ormultivalent, saturated or partially unsaturated, but not aromatic ringsystem wherein a ring originating from a particular annular carbon ofanother ring, and such that two rings only share one atom.

For example, as depicted below in Structure a-1 and Structure a-2, asaturated ring system, ring B and B′ is termed as “fused bicyclyl”,whereas ring A′ and ring B share an atom between the two saturated ringsystem, which terms as a “spirocyclyl” or “spiro bicyclyl”, and ring Cand C′ is termed as “bridged bicyclyl”. Each ring in the fused bicyclyl,the spiro bicyclyl or the bridged bicyclyl can be either a carbocyclylor a heterocyclyl, and each ring is optionally substituted independentlywith one or more substituents described herein.

The term “heterocycloalkyl” refers to a monovalent or multivalentsaturated ring having 3 to 12 ring atoms as a monocyclic, bicyclic, ortricyclic ring system in which at least one ring atom is selected fromnitrogen, sulfur and oxygen and which may, unless otherwise specified,be carbon or nitrogen linked, and of which a —CH₂— group can optionallybe replaced by a —C(═O)— group. Ring sulfur atoms may be optionallyoxidized to form S-oxides. Ring nitrogen atoms maybe optionally oxidizedto form N-oxides. Some non-limiting examples of heterocycloalkyl includeazetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl,imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl,piperazinyl, morpholinyl, dioxanyl, dithianyl, dithiolanyl,isoxazolidinyl, isothiazolidinyl, 1,2-oxazinanyl, 1,2-thiazinanyl,hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, oxepanyl,thiepanyl, oxazepinyl (e.g. 1,4-oxazepinyl, 1,2-oxazepinyl), diazepinyl(e.g. 1,4-diazepinyl, 1,2-diazepinyl), dioxpinyl (e.g. 1,4-dioxpinyl,1,2-dioxpinyl), thiazepinyl (e.g. 1,4-thiazepinyl, 1,2-thiazepinyl),2-azaspiro[4.4]nonanyl, 1,6-dioxaspiro[4.4]nonanyl,2-azaspiro[4.5]decanyl, 8-azaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl,3-azaspiro[5.5]undecanyl, 2-azaspiro[5.5]undecanyl,2-octahydro-1H-isoindolyl, octahydrocyclopenta[c]pyrrolyl,hexahydrofuro[3,2-b]furanyl, decahydroisoquinolinyl,hexahydrofuro[2,3-b]furanyl, and the like. The heterocycloalkyl groupmay be optionally substituted with one or more substituents describedherein.

In one embodiment, heterocycloalkyl refers to a 7-12 memberedheterocycloalkyl, which refers to a monovalent or multivalent saturatedspiro, fused or bridged heterobicycloalkyl, containing 7-12 ring atoms,of which at least one ring atom is selected from nitrogen, sulfur andoxygen and which may, unless otherwise specified, be carbon or nitrogenlinked, and of which a —CH₂— group can optionally be replaced by a—C(═O)— group. Ring sulfur atoms may be optionally oxidized to formS-oxides. Ring nitrogen atoms maybe optionally oxidized to formN-oxides. The 7-12 membered heterocycloalkyl group may be optionallysubstituted with one or more substituents described herein.

In one embodiment, heterocycloalkyl refers to a 4-7 memberedheterocycloalkyl, which refers to a monovalent or multivalent saturatedheterocyclyl ring containing 4-7 ring atoms, of which at least one ringatom is selected from nitrogen, sulfur and oxygen and which may, unlessotherwise specified, be carbon or nitrogen linked, and of which a —CH₂—group can optionally be replaced by a —C(═O)— group. Ring sulfur atomsmay be optionally oxidized to form S-oxides. Ring nitrogen atoms maybeoptionally oxidized to form N-oxides. Some non-limiting examples of 4-7membered heterocycloalkyl include azetidinyl, oxetanyl, thietanyl,pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl,morpholinyl, dioxanyl, dithianyl, dithiolanyl, isoxazolidinyl,isothiazolidinyl, hexahydropyridazinyl, homopiperazinyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, andthiazepinyl. The 4-7 membered heterocycloalkyl group may be optionallysubstituted with one or more substituents described herein.

In another embodiment, heterocycloalkyl refers to a 7-12 membered spiroheterobicycloalkyl, which refers to a monovalent or multivalentsaturated spiro heterobicycloalkyl ring containing 7-12 ring atoms, ofwhich at least one ring atom is selected from nitrogen, sulfur andoxygen. Unless otherwise specified, the 7-12 membered spiroheterobicycloalkyl maybe carbon or nitrogen linked, and of which a —CH₂—group can optionally be replaced by a —C(═O)— group. Ring sulfur atomsmay be optionally oxidized to form S-oxides. Ring nitrogen atoms maybeoptionally oxidized to form N-oxides. Some non-limiting examples of 7-12membered spiro heterobicycloalkyl include 2-azaspiro[4.4]nonanyl,1,6-dioxaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl,8-azaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl,3-azaspiro[5.5]undecanyl, 2-azaspiro[5.5]undecanyl, and the like. The7-12 membered spiro heterobicycloalkyl group may be optionallysubstituted with one or more substituents described herein.

In another embodiment, heterocycloalkyl refers to a 7-12 membered fusedheterobicycloalkyl, which refers to a monovalent or multivalentsaturated fused heterobicycloalkyl ring containing 7-12 ring atoms, ofwhich at least one ring atom is selected from nitrogen, sulfur andoxygen. Unless otherwise specified, the 7-12 membered fusedheterobicycloalkyl maybe carbon or nitrogen linked, and of which a —CH₂—group can optionally be replaced by a —C(═O)— group. Ring sulfur atomsmay be optionally oxidized to form S-oxides. Ring nitrogen atoms maybeoptionally oxidized to form N-oxides. Some non-limiting examples of 7-12membered fused heterobicycloalkyl include octahydro-1H-isoindolyl (e.g.octahydro-1H-isoindole-5-yl, octahydro-1H-isoindole-7-yl),octahydrocyclopenta[c]pyrrolyl (e.g. octahydrocyclopenta[c]pyrrole-5-yl,octahydrocyclopenta[c]pyrrole-2-yl), hexahydrofuro[3,2-b]furanyl (e.g.hexahydrofuro[3,2-b]furan-2-yl, hexahydrofuro[3,2-b]furan-3-yl),decahydroisoquinolinyl, hexahydrofuro[2,3-b]furanyl, and the like. The7-12 membered fused heterocybicloalkyl group may be optionallysubstituted with one or more substituents described herein.

In another embodiment, heterocycloalkyl refers to a 8-10 membered fusedheterobicycloalkyl, which refers to a monovalent or multivalentsaturated fused heterobicycloalkyl ring containing 8-10 ring atoms, ofwhich at least one ring atom is selected from nitrogen, sulfur andoxygen. Unless otherwise specified, the 8-10 membered fusedheterobicycloalkyl maybe carbon or nitrogen linked, and of which a —CH₂—group can optionally be replaced by a —C(═O)— group. Ring sulfur atomsmay be optionally oxidized to form S-oxides. Ring nitrogen atoms maybeoptionally oxidized to form N-oxides. Some non-limiting examples of 8-10membered fused heterobicycloalkyl include octahydro-1H-isoindolyl (e.g.octahydro-1H-isoindole-5-yl, octahydro-1H-isoindole-7-yl),octahydrocyclopenta[c]pyrrolyl (e.g. octahydrocyclopenta[c]pyrrole-5-yl,octahydrocyclopenta[c]pyrrole-2-yl), hexahydrofuro[3,2-b]furanyl (e.g.hexahydrofuro[3,2-b]furan-2-yl, hexahydrofuro[3,2-b]furan-3-yl),decahydroisoquinolinyl, hexahydrofuro[2,3-b]furanyl, and the like. The8-10 membered fused heterocybicloalkyl group may be optionallysubstituted with one or more substituents described herein.

The term “n membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a 6membered heterocycloalkyl and 1,2,3,4-tetrahydronaphthalenyl is anexample of a 10 membered carbocyclyl group.

The term “unsaturated” refers to a moiety having one or more units ofunsaturation.

The term “heteroatom” refers to one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon, including any oxidized form of nitrogen, sulfur,or phosphorus; the quaternized form of any basic nitrogen; or asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as inN-substituted pyrrolidinyl).

The term “halogen” refers to Fluoro (F), Chloro (Cl), Bromo (Br), orIodo (I). The term “azido” or “N₃” refers to an azide moiety. Thisradical may be attached, for example, to a methyl group to formazidomethane (methyl azide, MeN₃); or attached to a phenyl group to formphenyl azide (PhN₃).

The term “aryl” refers to monocyclic, bicyclic, and tricycliccarbocyclic ring systems having a total of 6 to 14 ring members,preferably, 6 to 12 ring members, and more preferably 6 to 10 ringmembers, wherein at least one ring in the system is aromatic, whereineach ring in the system contains 3 to 7 ring members and that has one ormore points of attachment to the rest of the molecule. The term “aryl”may be used interchangeably with the term “aryl ring” or “aromaticring”. Some non-limiting examples of the aryl group would includephenyl, naphthyl, and anthracenyl. The aryl radical is optionallysubstituted independently with one or more substituents describedherein.

The term “heteroaryl” or “heteroaromatic ring” refers to monocyclic,bicyclic, and tricyclic ring systems having a total of 5 to 12 ringmembers, preferably, 5 to 10 ring members, and more preferably 5 to 6ring members, wherein at least one ring in the system is aromatic, atleast one aromatic ring in the system contains one or more heteroatoms,wherein each ring in the system contains 5 to 7 ring members and thathas one or more points of attachment to the rest of the molecule. Theterm “heteroaryl” may be used interchangeably with the term “heteroarylring” or the term “heteroaromatic ring”. In one embodiment, heteroarylrefers to a 5-12 membered heteroaryl comprises 1, 2, 3 or 4 heteroatomsindependently selected from O, S and N. In another embodiment,heteroaryl refers to a 5-10 membered heteroaryl comprises 1, 2, 3 or 4heteroatoms independently selected from O, S and N. In anotherembodiment, heteroaryl refers to a 5-6 membered heteroaryl comprises 1,2, 3 or 4 heteroatoms independently selected from O, S and N. Theheteroaryl radical is optionally independently substituted with one ormore substituents described herein.

Some non-limiting examples of the 5-12 membered heteroaryl group includefollowing bicyclyl heteroaryl: benzimidazolyl, benzofuryl,benzothiophenyl, indolyl (e.g., 2-indolyl, 3-indolyl, 4-indolyl,5-indolyl, 6-indolyl, 7-indolyl), purinyl, quinolinyl (e.g.,2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g.,1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl), indazolyl (e.g.,3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl),imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[1,5-a]pyrimidyl, imidazo[1,2-b]pyridazinyl,[1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl and[1,2,4]triazolo[1,5-a]pyridinyl, purinyl, and the like. 5-12 memberedheteroaryl group also include 5-6 membered heteroaryl group. Somenon-limiting examples of the 5-6 membered heteroaryl group includefuranyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., 1-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g.,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g., 2-oxazolyl,4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridonyl,pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl),pyrimidonyl, pyrimidinedionyl, pyridazinyl (e.g., 3-pyridazinyl,4-pyridazinyl), pyrazinyl (2-pyrazinyl, 3-pyrazinyl), thiazolyl (e.g.,2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (e.g., 5-tetrazolyl),triazolyl (e.g., 2-triazolyl and 5-triazolyl), thienyl (e.g., 2-thienyl,3-thienyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl,5-pyrazolyl), pyrazolonyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl,1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl,1,3,5-triazinyl, and the like.

The term “azolyl” refers to a 5-membered or 9-membered heteroaryl ringsystem containing at least two heteroatoms and wherein at least oneheteroatoms is nitrogen atom. Some non-limiting examples of the azolylinclude pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl,thiazolyl, isothiazolyl, thiadiazolyl, diazolyl, triazolyl, indazolyl,pyrazolo[3,4-b]pyridinyl, pyrazolo[4,3-c]pyridinyl,1H-imidazo[4,5-b]pyridinyl and 1H-benzo[d]imidazolyl, and the like.

The term “carboxy” or “carboxyl”, whether used alone or with otherterms, such as “carboxyalkyl”, refers to —CO₂H. The term “carbonyl”,whether used alone or with other terms, such as “aminocarbonyl”, denotes—(C═O)—.

The term “alkylamino” embraces “N-alkylamino” and “N,N-dialkylamino”where amino groups are independently substituted with one alkyl radicalor with two alkyl radicals, respectively. In one embodiment, alkylaminohas one or two alkyl radicals of one to twelve carbon atoms, attached toa nitrogen atom. In another embodiment, alkylamino are “loweralkylamino” radicals having one or two alkyl radicals of one to sixcarbon atoms, attached to a nitrogen atom. In another embodiment,alkylamino are alkylamino radicals having one or two alkyl radicals ofone to four carbon atoms, attached to a nitrogen atom. In still anotherembodiment, alkylamino are alkylamino radicals having one or two alkylradicals of one to three carbon atoms, attached to a nitrogen atom. Somenon-limiting examples of alkylamino include N-methylamino (—NHCH₃),N-ethylamino, N,N-dimethylamino (—NH(CH₃)₂), N,N-diethylamino,N-ethylpropan-2-amino and the like.

The term “arylamino” refers to amino groups, which have been substitutedwith one or two aryl radicals, such as N-phenylamino. The arylaminoradicals may be further substituted on the aryl ring portion of theradical.

The term “aminoalkyl” refers to linear or branched alkyl radicals havingone to about twelve carbon atoms any one of which may be substitutedwith one or more amino radicals. In one embodiment, the aminoalkyl has1-12 carbon atoms and one or more amino radicals. In another embodiment,the aminoalkyl radicals are “lower aminoalkyl” radicals having 1-6carbon atoms and one or more amino radicals. In another embodiment,aminoalkyl has 1-4 carbon atoms and one or more amino radicals. In stillanother embodiment, aminoalkyl has 1-3 carbon atoms and one or moreamino radicals. Examples of such radicals include aminomethyl (—CH₂NH₂),aminoethyl (—CH₂CH₂NH₂, —CH(NH₂)CH₃), aminopropyl, aminobutyl andaminohexyl.

As described herein, a bond drawn from a substituent to the center ofone ring within a ring system (as shown below in Structure b) representssubstitution of the substituent at any substitutable position on thering system. For example, as depicted below, Figure b representspossible substitution in any of the positions on the ring D shown inFigure c˜Structure e.

As described herein, a connecting bond drawn from the center of one ringwithin a ring system (as shown in Structure f, wherein each X and X′ isindependently CH₂, NH or O) represents connection of the connecting bondattached to the rest of the molecule at any substitutable position onthe ring system. For example, Structure f represents possible connectionattached to the rest of the molecule in any of the position on ring Eand ring F (as shown in Structure f-1˜Structure f-8).

As described herein, two connecting bonds drawn from the center of onering within a ring system (as shown in Structure i) representsconnection of the connecting bonds attached to the rest of the moleculeat any two substitutable positions on the ring system, and the twoconnecting points (point Q and point Q′) can exchange. For example,Structure i represents possible connection attached to the rest of themolecule in any two of the positions on ring G.

The term “protecting group” or “PG” refers to a substituent that iscommonly employed to block or protect a particular functionality whilereacting other functional groups on the compound. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxy-carbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and9-fluorenylmethylenoxy-carbonyl (Fmoc). Similarly, a “hydroxy-protectinggroup” refers to a substituent of a hydroxy group that blocks orprotects the hydroxy functionality. Suitable protecting groups includeacetyl and silyl. A “carboxy-protecting group” refers to a substituentof the carboxy group that blocks or protects the carboxy functionality.Common carboxy-protecting groups include —CH₂CH₂SO₂Ph, cyanoethyl,2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxy-methyl,2-(p-toluenesulfonyl)-ethyl, 2-(p-nitrophenylsulfenyl)-ethyl,2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a generaldescription of protecting groups and their use, see T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1991; and P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

The term “prodrug” as used herein, represents a compound that istransformed in vivo into a compound of Formula (I) or Formula (II). Sucha transformation can be affected, for example, by hydrolysis in blood orenzymatic transformation of the prodrug form to the parent form in bloodor tissue. Prodrugs of the compounds disclosed herein may be, forexample, esters. Esters that may be utilized as prodrugs in the presentinvention are phenyl esters, aliphatic (C₁-C₂₄) esters, acyloxymethylesters, carbonates, carbamates, and amino acid esters. For example, acompound disclosed herein that contains an OH group may be acylated atthis position in its prodrug form. Other prodrug forms includephosphates, such as, for example those phosphates resulting from thephosphonation of an OH group on the parent compound. A thoroughdiscussion of prodrugs is provided in Higuchi et al., Pro-drugs as NovelDelivery Systems, Vol. 14, A.C.S. Symposium Series; Roche et al.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987; Rautio et al., Prodrugs: Designand Clinical Applications, Nat. Rev. Drug Discovery, 2008, 7, 255-270,and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med.Chem., 2008, 51, 2328-2345, all of which are incorporated herein byreference.

A “metabolite” refers to a product produced through metabolism in thebody of a specified compound or salt thereof. The metabolites of acompound may be identified using routine techniques known in the art andtheir activities determined using tests such as those described herein.Such products may result for example from the oxidation, reduction,hydrolysis, amidation, deamidation, esterification, deesterification,enzymatic cleavage, and the like, of the administered compound.Accordingly, the invention includes metabolites of compounds disclosedherein, including compounds produced by a process comprising contactinga compound disclosed herein with a mammal for a period of timesufficient to yield a metabolic product thereof.

A “pharmaceutically acceptable salt” refers to organic or inorganicsalts of a compound disclosed herein. The pharmaceutically acceptablesalts are well known in the art. For example, Berge et al., describepharmaceutically acceptable salts in detail in J. Pharm. Sci., 1977, 66,1-19, which is incorporated herein by reference. Some non-limitingexamples of the pharmaceutically acceptable salt include salts of anamino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid.

Other examples of the pharmaceutically acceptable salt include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike.

Pharmaceutically acceptable salts derived from appropriate bases includealkali metal, alkaline earth metal, ammonium and N⁺(C₁-C₄ alkyl)₄ salts.This invention also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. Water oroil-soluble or dispersible products may be obtained by suchquaternization. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further examples of the pharmaceutically acceptable salt include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, C₁-C₈ sulfonate and aryl sulfonate.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound disclosed herein. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.The term “hydrate” refers to the complex where the solvent molecule iswater.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the onset or development or progression of the disease ordisorder.

“Inflammatory disorder/disease” as used herein can refer to any disease,disorder, or syndrome in which an excessive or unregulated inflammatoryresponse leads to excessive inflammatory symptoms, host tissue damage,or loss of tissue function. “Inflammatory disorder/disease” also refersto a pathological state mediated by influx of leukocytes and/orneutrophil chemotaxis.

“Inflammation” as used herein refers to a localized, protective responseelicited by injury or destruction of tissues, which serves to destroy,dilute, or wall off (i.e. sequester) both the injurious agent and theinjured tissue. Inflammation is notably associated with influx ofleukocytes and/or neutrophil chemotaxis. Inflammation can result frominfection with pathogenic organisms and viruses and from noninfectiousmeans such as trauma or reperfusion following myocardial infarction orstroke, immune response to foreign antigen, and autoimmune responses.Accordingly, inflammatory disorders amenable to treatment with thecompounds disclosed herein encompass disorders associated with reactionsof the specific defense system as well as with reactions of thenonspecific defense system.

“Specific defense system” refers to the component of the immune systemthat reacts to the presence of specific antigens. Examples ofinflammation resulting from a response of the specific defense systeminclude the classical response to foreign antigens, autoimmune diseases,and delayed type hypersensitivity response mediated by T-cells. Chronicinflammatory diseases, the rejection of solid transplanted tissue andorgans, e.g., kidney and bone marrow transplants, and graft versus hostdisease (GVHD), are further examples of inflammatory reactions of thespecific defense system.

“Autoimmune disease” as used herein refers to any group of disorders inwhich tissue injury is associated with humoral or cell-mediatedresponses to the body's own constituents.

“Allergic disease” as used herein refers to any symptoms, tissue damage,or loss of tissue function resulting from allergy. “Arthritic disease”as used herein refers to any disease that is characterized byinflammatory lesions of the joints attributable to a variety ofetiologies. “Dermatitis” as used herein refers to any of a large familyof diseases of the skin that are characterized by inflammation of theskin attributable to a variety of etiologies. “Transplant rejection” asused herein refers to any immune reaction directed against graftedtissue, such as organs or cells (e.g., bone marrow), characterized by aloss of function of the grafted and surrounding tissues, pain, swelling,leukocytosis, and thrombocytopenia. The therapeutic methods of thepresent invention include methods for the treatment of disordersassociated with inflammatory cell activation.

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byunregulated cell growth. A “tumor” comprises one or more cancerouscells. Examples of cancer include, but are not limited to, carcinoma,lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. Moreparticular examples of such cancers include squamous cell cancer (e.g.,epithelial squamous cell cancer), lung cancer including small-cell lungcancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lungand squamous carcinoma of the lung, cancer of the peritoneum,hepatocellular cancer, gastric or stomach cancer includinggastrointestinal cancer, pancreatic cancer, glioblastoma, cervicalcancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breastcancer, colon cancer, rectal cancer, colorectal cancer, endometrial oruterine carcinoma, salivary gland carcinoma, kidney or renal cancer,prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, analcarcinoma, penile carcinoma, as well as head and neck cancer.

Description of Compounds of the Invention

In the present invention, novel compounds which are inhibitors ofprotein kinase activity, in particular JAK kinases, FLT3 kinase andAurora kinases activity, are disclosed. Compounds which are proteinkinase inhibitors may be useful in the treatment of diseases associatedwith inappropriate protein kinase activity, in particular inappropriateJAK, FLT3 and Aurora kinases activity, for example in the treatment andprevention of diseases mediated by JAK kinases, FLT3 kinase and Aurorakinases involved signalling pathways. Such diseases includeproliferative disease, autoimmune disease, allergic disease,inflammatory disease, transplantation rejection, and theirco-morbidities. In particular, a compound of the present invention maybe useful in the treatment of diseases such as cancer, polycythemiavera, essential thrombocytosis, myelofibrosis, chronic myelogenousleukemia (CML), acute myeloid leukemia (AML), acute lymphocytic leukemia(ALL), chronic obstruction pulmonary disease (COPD), asthma, systemicand cutaneous lupus erythematosis, lupus nephritis, dermatomyositis,Sjogren's syndrome, psoriasis, type I diabetes mellitus, allergic airwaydisease, sinusitis, eczema, hives, food allergies, allergies to insectvenom, inflammatory bowel syndrome, Crohn's disease, rheumatoidarthritis, juvenile arthritis, psoriatic arthritis, organ transplantrejection, tissue transplant rejection, cell transplant rejection, toname a few.

In one embodiment, the compounds disclosed herein may show potentinhibitory activities against one or more protein kinases.

In one aspect, provided herein is a compound having Formula (I):

or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, apharmaceutically acceptable salt or a prodrug thereof, wherein each ofZ, Z¹, A and R¹ is as defined herein.

In one embodiment, Z is C₇-C₁₂ spiro bicycloalkyl, C₇-C₁₂ fusedbicycloalkyl, 7-12 membered spiro heterobicyclyl or 7-12 membered fusedheterobicycloalkyl, wherein Z is optionally substituted by 1, 2, 3, 4 or5 R² groups;

Z¹ is H, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl or 3-12 membered heterocyclyl,wherein each of the C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl and 3-12 memberedheterocyclyl is optionally independently substituted by 1, 2, 3, 4 or 5R^(2a) groups;

A is

R¹ is H, F, Cl, Br, I, N₃, CN, —NO₂, C₁-C₁₂ alkyl, C₁-C₁₂ alkoxyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, 3-12 memberedheterocyclyl, C₆-C₁₂ aryl, 5-12 membered heteroaryl, —NR^(9a)R^(9b),—OR^(9c), —C(═O)R^(9d), —OC(═O)R^(9d), —C(═O)OR^(9c),—N(R^(9e))C(═O)R^(9d), —C(═O)NR^(9a)R^(9b),—N(R^(9e))C(═O)NR^(9a)R^(9b), —S(═O)₂R^(9f), —N(R^(9e))S(═O)₂R^(9f) or—S(═O)₂NR^(9a)R^(9b), wherein each of the C₁-C₁₂ alkyl, C₁-C₁₂ alkoxyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, 3-12 memberedheterocyclyl, C₆-C₁₂ aryl and 5-12 membered heteroaryl is optionallyindependently substituted by 1, 2, 3, 4 or 5 R¹¹ groups;

each R² is independently F, Cl, Br, I, —NO₂, N₃, CN, —OH, —NH₂,—C(═O)CH₂CN, —NHC(═O)CH₂CN, —N(CH₃)C(═O)CH₂CN, C₁-C₁₂ alkyl, C₂-C₁₂alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂ alkoxyl, C₃-C₁₂ cycloalkyl, 3-12membered heterocyclyl, C₆-C₁₂ aryl, 5-12 membered heteroaryl,—NR^(10a)R^(10b), —O—(C₀-C₄ alkylene)-R^(10c), —O—(C₁-C₄alkylene)-OR^(10c), —C(═O)R^(10d), —OC(═O)R^(10d),—N(R^(10e))C(═O)R^(10d), —C(═O)NR^(10a)R^(10b),—N(R^(10e))C(═O)NR^(10a)R^(10b), C(═O)N(R^(10e))C(═O)R^(10d),—S(═O)₂R^(10f), —N(R^(10e))S(═O)₂R^(10f) or —S(═O)₂NR^(10a)R^(10b), ortwo adjacent R² taken together with the atoms to which they are attachedform a C₃-C₁₂ cycloalkyl or 3-12 membered heterocycloalkyl group,wherein each of the C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂alkoxyl, C₃-C₁₂ cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryl,5-12 membered heteroaryl, and 3-12 membered heterocycloalkyl group isoptionally independently substituted by 1, 2, 3, 4 or 5 R¹¹ groups;

each R^(2a) is independently H, F, Cl, Br, I, —NO₂, N₃, CN, —OH, —NH₂,C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂ alkoxyl, C₃-C₁₂cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryl, 5-12 memberedheteroaryl, —NR^(10a)R^(10b), —O—(C₀-C₄ alkylene)-R^(10c), —O—(C₁-C₄alkylene)-OR^(10c), —C(═O)R^(10d), —OC(═O)R^(10d),—N(R^(10e))C(═O)R^(10d), —C(═O)NR^(10a)R^(10b),—N(R^(10e))C(═O)NR^(10a)R^(10b), —C(═O)N(R^(10e))C(═O)R^(10d),—S(═O)₂R^(10f), —N(R^(10e))S(═O)₂R^(10f) or —S(═O)₂NR^(10a)R^(10b),wherein each of the C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂alkoxyl, C₃-C₁₂ cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryl,5-12 membered heteroaryl, and 3-12 membered heterocycloalkyl group isoptionally independently substituted by 1, 2, 3, 4 or 5 R¹¹ groups;

R³ is H, C₃-C₁₂ hydroxyalkyl, C₃-C₁₂ alkyl, C₁-C₁₂ haloalkyl, C₁-C₁₂aminoalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, whereineach of the C₃-C₁₂ hydroxyalkyl, C₃-C₁₂ alkyl, C₁-C₁₂ haloalkyl, C₁-C₁₂aminoalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂aryl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl isoptionally independently substituted by 1, 2, 3, 4 or 5 R¹¹ groups;

R⁴ is C₁-C₁₂ hydroxyalkyl, C₃-C₁₂ alkyl, C₁-C₁₂ haloalkyl, C₁-C₁₂aminoalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, wherein R⁴is optionally substituted by 1, 2, 3, 4 or 5 R¹¹ groups;

each of R⁵, R⁶, R⁷ and R⁸ is independently H, C₁-C₁₂ hydroxyalkyl,C₃-C₁₂ alkyl, C₁-C₁₂ haloalkyl, C₁-C₁₂ aminoalkyl, C₂-C₁₂ alkenyl,C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂aryl or 5-12 membered heteroaryl, wherein each of the C₁-C₁₂hydroxyalkyl, C₃-C₁₂ alkyl, C₁-C₁₂ haloalkyl, C₁-C₁₂ aminoalkyl, C₂-C₁₂alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, 3-12 membered heterocyclyl,C₆-C₁₂ aryl and 5-12 membered heteroaryl is optionally independentlysubstituted by 1, 2, 3, 4 or 5 R¹¹ groups;

each R^(3a), R^(4a), R^(5a), R^(6a), R^(7a) and R^(8a) is independentlyH, F, Cl, CN, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂alkoxyl, C₁-C₁₂ alkylamino, —(C₀-C₄ alkylene)-(C₃-C₁₂ cycloalkyl),—(C₀-C₄ alkylene)-(3-12 membered heterocyclyl), C₆-C₁₂ aryl, 5-12membered heteroaryl, —NR^(9a)R^(9b), —OR^(9c), —C(═O)R^(9d),—C(═O)OR^(9c), —N(R^(9e))C(═O)R^(9d), —C(═O)NR^(9a)R^(9b),—N(R^(9e))C(═O)NR^(9a)R^(9b), —S(═O)₂R^(9f), —N(R^(9e))S(═O)₂R^(9f) or—S(═O)₂NR^(9a)R^(9b), wherein each of the C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl,C₂-C₁₂ alkynyl, C₁-C₁₂ alkoxyl, C₁-C₁₂ alkylamino, —(C₀-C₄alkylene)-(C₃-C₁₂ cycloalkyl), —(C₀-C₄ alkylene)-(3-12 memberedheterocyclyl), C₆-C₁₂ aryl and 5-12 membered heteroaryl is optionallyindependently substituted by 1, 2, 3, 4 or 5 R¹¹ groups;

each R^(9a), R^(9b), R^(9c), R^(9e), R^(10a), R^(10b), R^(10c) andR^(10e) is independently H, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂alkynyl, C₁-C₁₂ alkoxyl, C₃-C₁₂ cycloalkyl, —(C₀-C₄ alkylene)-(C₃-C₁₂cycloalkyl), —(C₀-C₄ alkylene)-(3-12 membered heterocyclyl), —(C₀-C₄alkylene)-(C₆-C₁₀ aryl) or —(C₀-C₄ alkylene)-(5-12 membered heteroaryl),or R^(9a) and R^(9b), R^(10a) and R^(10b) taken together with thenitrogen atom to which they are attached form a 3-12 memberedheterocyclyl group, wherein each of the C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl,C₂-C₁₂ alkynyl, C₁-C₁₂ alkoxyl, C₃-C₁₂ cycloalkyl, —(C₀-C₄alkylene)-(C₃-C₁₂ cycloalkyl), —(C₀-C₄ alkylene)-(3-12 memberedheterocyclyl), —(C₀-C₄ alkylene)-(C₆-C₁₀ aryl), —(C₀-C₄ alkylene)-(5-12membered heteroaryl) and 3-12 membered heterocyclyl group is optionallysubstituted by 1, 2, 3 or 4 substitutents independently selected from F,Cl, Br, CN, N₃, —NO₂, —OH, —NH₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl and C₁-C₆ alkylamino;

each R^(9d), R^(9f), R^(10d) and R^(10f) is independently C₁-C₁₂ alkyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂ alkoxyl, C₃-C₁₂ cycloalkyl, 3-12membered heterocyclyl, C₆-C₁₂ aryl, 5-12 membered heteroaryl, —(C₁-C₄alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄ alkylene)-(3-12 memberedheterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl) or —(C₁-C₄alkylene)-(5-12 membered heteroaryl), wherein each of the abovesubstituents is optionally substituted by 1, 2, 3 or 4 substitutentsindependently selected from F, Cl, Br, CN, N₃, —OH, —NH₂, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl andC₁-C₆ alkylamino;

each R¹¹ is independently F, Cl, Br, I, CN, —NO₂, N₃, —OH, —NH₂, C₁-C₁₂alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂ haloalkyl, C₃-C₁₂cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl, 5-12 memberedheteroaryl, C₁-C₁₂ aminoalkyl, C₁-C₁₂ alkylamino, C₁-C₁₂ alkoxyl, C₁-C₁₂hydroxyalkyl, —NH(C₀-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —NH(C₀-C₄alkylene)-(C₆-C₁₂ aryl), —NH(C₀-C₄ alkylene)-(3-12 memberedheterocyclyl), —NH(C₀-C₄ alkylene)-(5-12 membered heteroaryl), —N[(C₀-C₄alkylene)-(C₃-C₁₂ cycloalkyl)]₂, —N[(C₀-C₄ alkylene)-(C₆-C₁₂ aryl)]₂,—N[(C₀-C₄ alkylene)-(3-12 membered heterocyclyl)]₂, —N[(C₀-C₄alkylene)-(5-12 membered heteroaryl)]₂, —O—(C₀-C₄ alkylene)-(C₃-C₁₂cycloalkyl), —O—(C₀-C₄ alkylene)-(C₆-C₁₂ aryl), —O—(C₀-C₄alkylene)-(3-12 membered heterocyclyl) or —O—(C₀-C₄ alkylene)-(5-12membered heteroaryl); and

each m is independently 0, 1 or 2.

In another embodiment, Z is 8-11 membered spiro heterobicyclyl or 8-10membered fused heterobicycloalkyl, wherein Z is optionally substitutedby 1, 2, 3 or 4 R² groups.

In one embodiment, Z is:

or a stereoisomer thereof, wherein each X, X′, X², and X³ isindependently —CH₂—, —NH— or —O—, with the proviso that X² and X³ arenot —O— simultaneously; and wherein Z is optionally substituted by 1, 2or 3 R² groups.

In another embodiment, Z is:

or a stereoisomer thereof, and wherein Z is optionally substituted by 1,2 or 3 R² groups.

In one embodiment, Z¹ is H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl or 4-7membered heterocyclyl, wherein each of the C₁-C₆ alkyl, C₃-C₆ cycloalkyland 4-7 membered heterocyclyl is optionally independently substituted by1, 2 or 3 R^(2a) groups.

In another embodiment, Z¹ is H, methyl, ethyl, n-propyl, isopropyl orcyclopropyl.

In one embodiment, R¹ is H, F, Cl, Br, I, N₃, CN, —NO₂, C₁-C₆ alkyl,C₁-C₆ alkoxyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 4-7membered heterocyclyl, —NR^(9a)R^(9b), —OR^(9c), —C(═O)R^(9d),—C(═O)OR^(9c), —C(═O)NR^(9a)R^(9b), —S(═O)₂R^(9f) or—S(═O)₂NR^(9a)R^(9b), wherein each of the C₁-C₆ alkyl, C₁-C₆ alkoxyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and 4-7 memberedheterocyclyl is optionally independently substituted by 1, 2 or 3 R¹¹groups.

In another embodiment, each R² is independently F, Cl, Br, I, —NO₂, N₃,CN, —OH, —NH₂, —C(═O)CH₂CN, —NHC(═O)CH₂CN, —N(CH₃)C(═O)CH₂CN, C₁-C₆alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyl, C₃-C₆ cycloalkyl, 4-7 memberedheterocyclyl, phenyl, 5-6 membered heteroaryl, —NR^(10a)R^(10b),—O—(C₀-C₃ alkylene)-R^(10c), —O—(C₁-C₃ alkylene)-OR^(10c),—C(═O)R^(10d), —OC(═O)R^(10d), —N(R^(10e))C(═O)R^(10d),—C(═O)NR^(10a)R^(10b), —N(R^(10e))C(═O)NR^(10a)R^(10b),C(═O)N(R^(10e))C(═O)R^(10d), —S(═O)₂R^(10f), —N(R^(10e))S(═O)₂R^(10f) or—S(═O)₂NR^(10a)R^(10b), or two adjacent R² taken together with the atomsto which they are attached form a C₃-C₆ cycloalkyl or 4-7 memberedheterocycloalkyl group, wherein each of the C₁-C₆ alkyl, C₂-C₆ alkenyl,C₁-C₆ alkoxyl, C₃-C₆ cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl group isoptionally independently substituted by 1, 2 or 3 R¹¹ groups;

each R^(2a) is independently H, F, Cl, Br, I, —NO₂, N₃, CN, —OH, —NH₂,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyl, C₃-C₆ cycloalkyl, 4-7membered heterocyclyl, phenyl, 5-6 membered heteroaryl,—NR^(10a)R^(10b), —O—(C₀-C₃ alkylene)-R^(10c), —O—(C₁-C₃alkylene)-OR^(10c), —C(═O)R^(10d), —OC(═O)R^(10d),—N(R^(10e))C(═O)R^(10d), —C(═O)NR^(10a)R^(10b),—N(R^(10e))C(═O)NR^(10a)R^(10b), C(═O)N(R^(10e))C(═O)R^(10d),—S(═O)₂R^(10f), —N(R^(10e))S(═O)₂R^(10f) or —S(═O)₂NR^(10a)R^(10b).

In one embodiment, R³ is H, C₃-C₆ hydroxyalkyl, C₃-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ aminoalkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, phenyl,4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein each ofthe C₃-C₆ hydroxyalkyl, C₃-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ aminoalkyl,C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, phenyl, 4-7 membered heterocyclyl and5-6 membered heteroaryl is optionally independently substituted by 1, 2or 3 R¹¹ groups.

In another embodiment, R³ is H, —CH₂C(CH₃)₂OH, —(CH₂)₂CH₂OH,—CH₂CH(OH)CH₃, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl,pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, pyrrolyl oroxazolyl, wherein each of the piperidinyl, pyrrolidinyl, morpholinyl,piperazinyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, pyrrolyl oroxazolyl is optionally independently substituted by 1, 2 or 3 R¹¹groups.

In one embodiment, R⁴ is C₁-C₆ hydroxyalkyl, C₃-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ aminoalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, phenyl, 4-7 membered heterocyclyl or 5-6 memberedheteroaryl, wherein R⁴ is optionally substituted by 1, 2, or 3 R¹¹groups.

In another embodiment, each of R⁵, R⁶, R⁷ and R⁸ is independently H,C₁-C₆ hydroxyalkyl, C₃-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ aminoalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 4-7 memberedheterocyclyl, phenyl or 5-6 membered heteroaryl, wherein each of theC₁-C₆ hydroxyalkyl, C₃-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ aminoalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 4-7 memberedheterocyclyl, phenyl and 5-6 membered heteroaryl is optionallyindependently substituted by 1, 2 or 3 R¹¹ groups.

In one embodiment, each R^(3a), R^(4a), R^(5a), R^(6a), R^(7a) andR^(8a) is independently H, F, Cl, CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆alkoxyl, C₁-C₆ alkylamino, —(C₀-C₃ alkylene)-(C₃-C₆ cycloalkyl), —(C₀-C₃alkylene)-(4-7 membered heterocyclyl), phenyl, 5-6 membered heteroaryl,—NR^(9a)R^(9b), —OR^(9c), —C(═O)R^(9d), —C(═O)OR^(9c),—C(═O)NR^(9a)R^(9b), —S(═O)₂R^(9f) or —S(═O)₂NR^(9a)R^(9b), wherein eachof the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyl, C₁-C₆ alkylamino,—(C₀-C₃ alkylene)-(C₃-C₆ cycloalkyl), —(C₀-C₃ alkylene)-(4-7 memberedheterocyclyl), phenyl and 5-6 membered heteroaryl is optionallyindependently substituted by 1, 2 or 3 R¹¹ groups.

In another embodiment, each R^(9a), R^(9b), R^(9c), R^(9e), R^(10a),R^(10b), R^(10c) and R^(10e) is independently H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₃-C₆ cycloalkyl, —(C₀-C₃alkylene)-(C₃-C₆ cycloalkyl), —(C₀-C₃ alkylene)-(4-7 memberedheterocyclyl), —(C₀-C₃ alkylene)-phenyl, —(C₀-C₃ alkylene)-(5-6 memberedheteroaryl), or R^(9a) and R^(9b), R^(10a) and R^(10b) taken togetherwith the nitrogen atom to which they are attached form a 4-7 memberedheterocyclyl group, wherein each of the C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₃-C₆ cycloalkyl, —(C₀-C₃ alkylene)-(C₃-C₆cycloalkyl), —(C₀-C₃ alkylene)-(4-7 membered heterocyclyl), —(C₀-C₃alkylene)-phenyl, —(C₀-C₃ alkylene)-(5-6 membered heteroaryl), and 4-7membered heterocyclyl group is optionally substituted by 1, 2 or 3substitutents independently selected from F, Cl, Br, CN, N₃, —NO₂, —OH,—NH₂, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃ hydroxyalkyl,C₁-C₃ aminoalkyl and C₁-C₃ alkylamino.

In one embodiment, each R^(9a), R^(9b), R^(9c), R^(9e), R^(10a),R^(10b), R^(10c) and R^(10e) is independently H, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, allyl,vinyl, propenyl, C₁-C₄ alkoxyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl,-methylene-cyclopropy, -ethylidene-cyclopropyl, -methylene-cyclobutyl,-ethylidene-cyclobutyl, -methylene-cyclopentyl, -ethylidene-cyclopentyl,-methylene-cyclohexyl, -ethylidene-cyclohexyl, —(C₁-C₃ alkylene)-(4-7membered heterocyclyl), phenyl, pyridyl, pyridazinyl, pyrimidinyl,—(C₁-C₃ alkylene)-phenyl or —(C₁-C₃ alkylene)-(5-6 membered heteroaryl),wherein each of the methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, allyl, vinyl, propenyl, C₁-C₄ alkoxyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl,pyrrolidinyl, morpholinyl, piperazinyl, -methylene-cyclopropyl,-ethylidene-cyclopropyl, -methylene-cyclobutyl, -ethylidene-cyclobutyl,-methylene-cyclopentyl, -ethylidene-cyclopentyl, -methylene-cyclohexyl,-ethylidene-cyclohexyl, —(C₁-C₃ alkylene)-(4-7 membered heterocyclyl),phenyl, pyridyl, pyridazinyl, pyrimidinyl, —(C₁-C₃ alkylene)-phenyl and—(C₁-C₃ alkylene)-(5-6 membered heteroaryl) is optionally substituted by1, 2 or 3 substitutents independently selected from F, Cl, Br, CN, N₃,—NO₂, —OH, —NH₂, —CF₃, —OCH₃, —CH₂OH, —CH₂CH₂OH, —NHCH₃, —N(CH₃)₂ and—CH₂NH₂.

In another embodiment, each R^(9d), R^(9f), R^(10d) and R^(10f) isindependently C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxyl,C₃-C₆ cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 memberedheteroaryl, —(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)-(4-7membered heterocyclyl), —(C₁-C₃ alkylene)-phenyl or —(C₁-C₃alkylene)-(5-6 membered heteroaryl), wherein each of the abovesubstituents is optionally substituted by 1, 2 or 3 substitutentsindependently selected from F, Cl, Br, CN, N₃, —OH, —NH₂, C₁-C₃ alkyl,C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃ hydroxyalkyl, C₁-C₃ aminoalkyl andC₁-C₃ alkylamino.

In one embodiment, each R^(9d), R^(9f), R^(10d) and R^(10f) isindependently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,allyl, vinyl, propenyl, phenyl, piperidinyl, pyrrolidinyl, morpholinyl,piperazinyl, C₁-C₄ alkoxyl, -methylene-cyclopropy,-ethylidene-cyclopropyl, -methylene-cyclobutyl, -ethylidene-cyclobutyl,-methylene-cyclopentyl, -ethylidene-cyclopentyl, -methylene-cyclohexylor -ethylidene-cyclohexyl, wherein each of the above substituents isoptionally substituted by 1, 2 or 3 substitutents independently selectedfrom F, Cl, Br, CN, N₃, —OH, —NH₂, —CF₃, —OCH₃, —CH₂OH, —CH₂CH₂OH,—NHCH₃, —N(CH₃)₂ and —CH₂NH₂.

In another embodiment, each R¹¹ is independently F, Cl, Br, I, CN, NO₂,N₃, —OH, —NH₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄haloalkyl, C₃-C₆ cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6membered heteroaryl, C₁-C₄ aminoalkyl, C₁-C₄ alkylamino, C₁-C₄ alkoxyl,C₁-C₄ hydroxyalkyl, —NH(C₀-C₃ alkylene)-(C₃-C₆ cycloalkyl), —NH(C₀-C₃alkylene)-(4-7 membered heterocyclyl), —N[(C₀-C₃ alkylene)-(C₃-C₆cycloalkyl)]₂, —N[(C₀-C₃ alkylene)-(4-7 membered heterocyclyl)]₂,—O(C₀-C₃ alkylene)-(C₃-C₆ cycloalkyl) or —O(C₀-C₃ alkylene)-(4-7membered heterocyclyl).

In one embodiment, each R¹¹ is independently F, Cl, Br, I, CN, —NO₂, N₃,—OH, —NH₂, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy,ethyoxyl, n-propoxy, isopropoxy, hydroxymethyl, hydroxyethyl,methylamino, dimethylamino or aminomethyl.

In yet another embodiment, some non-limiting examples of the compounddisclosed herein, and their stereoisomer, tautomer, N-oxide, solvate,pharmaceutically acceptable salts and solvates thereof, are shown in thefollowing:

TABLE 1

(1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(33)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

(44)

(45)

(46)

(47)

In another aspect, provided herein is a compound having Formula (II):

or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, apharmaceutically acceptable salt or a prodrug thereof, wherein each ofW, W₁, R¹², R¹³ and n is as defined herein.

In one embodiment, W is C₇-C₁₂ spiro bicycloalkyl, C₇-C₁₂ fusedbicycloalkyl, 7-12 membered spiro heterobicyclyl or 7-12 membered fusedheterobicycloalkyl, wherein W is substituted by 1, 2, 3, 4 or 5 R¹⁴groups;

W₁ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyl, C₁-C₆ aminoalkyl,C₁-C₆ hydroxyalkyl, C₃-C₆ cycloalkyl or 4-7 membered heterocyclyl;

R¹² is H, F, Cl, Br, I, N₃, CN, —NO₂, C₁-C₁₂ alkyl, C₁-C₁₂ alkoxyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, 3-12 memberedheterocyclyl, C₆-C₁₂ aryl, 5-12 membered heteroaryl, —NR^(15a)R^(15b),—OR^(15c), —C(═O)R^(15d), —OC(═O)R^(15d), —C(═O)OR^(15c),—N(R^(15e))C(═O)R^(15d), —C(═O)NR^(15a)R^(15b),—N(R^(15e))C(═O)NR^(15a)R^(15b), —S(═O)₂R^(15f),—N(R^(15e))S(═O)₂R^(15f) or —S(═O)₂NR^(15a)R^(15b), wherein each of theC₁-C₁₂ alkyl, C₁-C₁₂ alkoxyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryl and 5-12 memberedheteroaryl is optionally independently substituted by 1, 2, 3, 4 or 5R¹⁷ groups;

each R¹³ is independently H, F, Cl, CN, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl,C₁-C₁₂ alkoxyl, —(C₀-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₀-C₄alkylene)-(3-12 membered heterocyclyl), C₆-C₁₂ aryl, 5-12 memberedheteroaryl, —NR^(15a)R^(15b), —OR^(15c), —C(═O)R^(15d), —C(═O)OR^(15c),—C(═O)NR^(15a)R^(15b), —S(═O)₂R^(15f), —N(R^(15e))S(═O)₂R^(15f) or—S(═O)₂NR^(15a)R^(15b), wherein each of the C₁-C₁₂ alkyl, C₂-C₁₂alkenyl, C₁-C₁₂ alkoxyl, —(C₀-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₀-C₄alkylene)-(3-12 membered heterocyclyl), C₆-C₁₂ aryl and 5-12 memberedheteroaryl is optionally independently substituted by 1, 2, 3, 4 or 5R¹⁷ groups;

each R¹⁴ is independently F, Cl, Br, I, NO₂, N₃, CN, C₃-C₁₂ alkyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂ hydroxyalkyl, C₃-C₁₂ alkoxyl,C₁-C₁₂ alkylamino, C₁-C₁₂ aminoalkyl, C₃-C₁₂ cycloalkyl, 4-7 memberedheterocyclyl, C₆-C₁₂ aryl, 6-cyanopyridazine-3-yl, —CH₂CN, —CH₂CH₂CN,—C(═O)R^(16d), —S(═O)₂R^(16e), —C(═O)NR^(16a)R^(16b),—S(═O)₂NR^(16a)R^(16b), —C(═O)O—R^(16c), —N(R^(16a))C(═O)R^(16f),—N(R^(16a))S(═O)₂R^(16g) or —OC(═O)R^(16f) wherein each of the —CH₂CN,—CH₂CH₂CN, C₃-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂hydroxyalkyl, C₃-C₁₂ alkoxyl, C₁-C₁₂ alkylamino, C₁-C₁₂ aminoalkyl,C₃-C₁₂ cycloalkyl, 4-7 membered heterocyclyl, C₆-C₁₂ aryl and6-cyanopyridazine-3-yl is optionally independently substituted by 1, 2,3, 4 or 5 R¹⁷ groups;

each R^(15a), R^(15b), R^(15c), R^(15e), R^(16a) and R^(16b) isindependently H, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryl, 5-12 memberedheteroaryl, —(C₁-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄alkylene)-(3-12 membered heterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl),or —(C₁-C₄ alkylene)-(5-12 membered heteroaryl), or R^(15a) and R^(15b),taken together with the nitrogen atom to which they are attached form a3-12 membered heterocyclyl group, wherein each of the C₁-C₁₂ alkyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, 3-12 memberedheterocyclyl, C₆-C₁₂ aryl, 5-12 membered heteroaryl, —(C₁-C₄alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄ alkylene)-(3-12 memberedheterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl), and —(C₁-C₄alkylene)-(5-12 membered heteroaryl) is optionally substituted by 1, 2or 3 substitutents independently selected from F, Cl, Br, CN, N₃, —NO₂,—OH, —NH₂, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄hydroxyalkyl, C₁-C₄ aminoalkyl and C₁-C₄ alkylamino;

each R^(15d) and R^(15f) is independently C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl,C₂-C₁₂ alkynyl, C₁-C₁₂ alkoxyl, —(C₀-C₄ alkylene)-(C₃-C₁₂ cycloalkyl),—(C₀-C₄ alkylene)-(3-12 membered heterocyclyl), —(C₀-C₄alkylene)-(C₆-C₁₂ aryl) or —(C₀-C₄ alkylene)-(5-12 membered heteroaryl),wherein each of the above substituents is optionally substituted by 1,2, 3 or 4 substitutents independently selected from F, Cl, Br, CN, N₃,—OH, —NH₂, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄hydroxyalkyl, C₁-C₄ aminoalkyl and C₁-C₄ alkylamino;

each R^(16d), R^(16e) and R^(16g) is independently C₂-C₁₂ alkyl, C₃-C₁₂cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryl, 5-12 memberedheteroaryl, —(C₁-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄alkylene)-(3-12 membered heterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl)or —(C₁-C₄ alkylene)-(5-12 membered heteroaryl), wherein each of theabove substituents is optionally substituted by 1, 2, 3 or 4substitutents independently selected from F, Cl, Br, CN, N₃, —OH, —NH₂,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ hydroxyalkyl, C₁-C₄aminoalkyl and C₁-C₄ alkylamino;

each R^(16c) and R^(16f) is independently C₁-C₃ alkyl, C₃-C₁₂cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryl, 5-12 memberedheteroaryl, —(C₁-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄alkylene)-(3-12 membered heterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl),or —(C₁-C₄ alkylene)-(5-12 membered heteroaryl), wherein each of theabove substituents is optionally substituted by 1, 2, 3 or 4substitutents independently selected from F, Cl, Br, CN, N₃, —OH, —NH₂,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ hydroxyalkyl, C₁-C₄aminoalkyl and C₁-C₄ alkylamino;

each R¹⁷ is independently F, Cl, Br, I, CN, NO₂, N₃, —OH, —NH₂, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,C₆-C₁₂ aryl, 4-7 membered heterocyclyl, 5-12 membered heteroaryl, C₁-C₆aminoalkyl, C₁-C₆ alkylamino, C₁-C₆ alkoxyl, C₁-C₆ hydroxyalkyl,—NH(C₀-C₄ alkylene)-(C₃-C₆ cycloalkyl), —NH(C₀-C₄ alkylene)-(4-7membered heterocyclyl), —N[(C₀-C₄ alkylene)-(C₃-C₆ cycloalkyl)]₂,—N[(C₀-C₄ alkylene)-(4-7 membered heterocyclyl)]₂, —O(C₀-C₄alkylene)-(C₃-C₆ cycloalkyl) or —O(C₀-C₄ alkylene)-(4-7 memberedheterocyclyl); and

n is 0, 1 or 2.

In another embodiment, W is 8-11 membered spiro heterobicyclyl or 8-10membered fused heterobicycloalkyl, wherein W is substituted by 1, 2, 3or 4 R¹⁴ groups.

In one embodiment, W is:

or a stereoisomer thereof, wherein each Y, Y′, Y² and Y³ isindependently —CH₂—, —NH— or —O—, with the proviso that Y² and Y³ arenot —O— simultaneously; and wherein W is substituted by 1, 2 or 3 R¹⁴groups.

In another embodiment, W is:

or a stereoisomer thereof, and wherein W is substituted by 1, 2 or 3 R¹⁴groups.

In one embodiment, W₁ is H, methyl, ethyl, n-propyl, isopropyl orcyclopropyl.

In another embodiment, R¹² is H, F, Cl, Br, I, N₃, CN, —NO₂, C₁-C₄alkyl, C₁-C₄ alkoxyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl,4-7 membered heterocyclyl, —NR^(15a)R^(15b), —OR^(15c), —C(═O)R^(15d),—C(═O)OR^(15c), —C(═O)NR^(15a)R^(15b), —S(═O)₂R^(15f), or—S(═O)₂NR^(15a)R^(15b), wherein each of the C₁-C₄ alkyl, C₁-C₄ alkoxyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl and 4-7 memberedheterocyclyl is optionally independently substituted by 1, 2 or 3 R¹⁷groups.

In one embodiment, each R¹³ is independently H, F, Cl, CN, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₁-C₄ alkoxyl, —(C₀-C₃ alkylene)-(C₃-C₆ cycloalkyl),—(C₀-C₃ alkylene)-(4-7 membered heterocyclyl), —NR^(15a)R^(15b),—OR^(15c), —C(═O)R^(15d), —C(═O)OR^(15c), —C(═O)NR^(15a)R^(15b),S(═O)₂R^(15f) or —S(═O)₂NR^(15a)R^(15b), wherein each of the C₁-C₄alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxyl, —(C₀-C₃ alkylene)-(C₃-C₆cycloalkyl) and —(C₀-C₃ alkylene)-(4-7 membered heterocyclyl) isoptionally independently substituted by 1, 2 or 3 R¹⁷ groups.

In another embodiment, each R¹⁴ is independently F, Cl, Br, I, —NO₂, N₃,CN, C₃-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ hydroxyalkyl, C₃-C₆alkoxyl, C₁-C₆ alkylamino, C₁-C₆ aminoalkyl, C₃-C₆ cycloalkyl, 4-7membered heterocyclyl, phenyl, 6-cyanopyridazine-3-yl, —CH₂CN,—CH₂CH₂CN, —C(═O)R^(16d), —S(═O)₂R^(16e), —C(═O)NR^(16a)R^(16b),—S(═O)₂NR^(16a)R^(16b), —C(═O)O—R^(16c), —N(R^(16a))C(═O)R^(16f),—N(R^(16a))S(═O)₂R^(16g) or —OC(═O)R^(16f), wherein each of the —CH₂CN,—CH₂CH₂CN, C₃-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆hydroxyalkyl, C₃-C₆ alkoxyl, C₁-C₆ alkylamino, C₁-C₆ aminoalkyl, C₃-C₆cycloalkyl, 4-7 membered heterocyclyl, phenyl and 6-cyanopyridazine-3-ylis optionally independently substituted by 1, 2 or 3 R¹⁷ groups.

In one embodiment, each R¹⁴ is independently F, Cl, Br, —NO₂, CN,

In another embodiment, each R^(15a), R^(15b), R^(15c), R^(15e), R^(16a)and R^(16b) is independently H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6membered heteroaryl, —(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl), —(C₁-C₃alkylene)-(4-7 membered heterocyclyl), —(C₁-C₃ alkylene)-phenyl or—(C₁-C₃ alkylene)-(5-6 membered heteroaryl), or R^(15a) and R^(15b),taken together with the nitrogen atom to which they are attached form a4-7 membered heterocyclyl group, wherein each of the C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, 4-7 membered heterocyclyl,phenyl, 5-6 membered heteroaryl, —(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl),—(C₁-C₃ alkylene)-(4-7 membered heterocyclyl), —(C₁-C₃ alkylene)-phenyland —(C₁-C₃ alkylene)-(5-6 membered heteroaryl) is optionallysubstituted by 1, 2 or 3 substitutents independently selected from F,Cl, Br, CN, N₃, —NO₂, —OH, —NH₂, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃alkoxy, C₁-C₃ hydroxyalkyl, C₁-C₃ aminoalkyl and C₁-C₃ alkylamino.

In one embodiment, each R^(15d) and R^(15f) is independently C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxyl, —(C₀-C₃alkylene)-(C₃-C₆ cycloalkyl), —(C₀-C₃ alkylene)-(4-7 memberedheterocyclyl), —(C₀-C₃ alkylene)-phenyl, or —(C₀-C₃ alkylene)-(5-6membered heteroaryl), wherein each of the above substituents isoptionally substituted by 1, 2 or 3 substitutents independently selectedfrom F, Cl, Br, CN, N₃, —OH, —NH₂, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃alkoxy, C₁-C₃ hydroxyalkyl, C₁-C₃ aminoalkyl and C₁-C₃ alkylamino.

In another embodiment, each R^(16d), R^(16e) and R^(16g) isindependently C₂-C₆ alkyl, C₃-C₆ cycloalkyl, 4-7 membered heterocyclyl,phenyl, 5-6 membered heteroaryl, —(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl),—(C₁-C₃ alkylene)-(4-7 membered heterocyclyl), —(C₁-C₃ alkylene)-phenyl,or —(C₁-C₃ alkylene)-(5-6 membered heteroaryl), wherein each of theabove substituents is optionally substituted by 1, 2, 3 or 4substitutents independently selected from F, Cl, Br, CN, N₃, —OH, —NH₂,C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃ hydroxyalkyl, C₁-C₃aminoalkyl and C₁-C₃ alkylamino.

In one embodiment, each R^(16c) and R^(16f) is independently C₁-C₃alkyl, C₃-C₆ cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 memberedheteroaryl, —(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)-(4-7membered heterocyclyl), —(C₁-C₃ alkylene)-phenyl, or —(C₁-C₃alkylene)-(5-6 membered heteroaryl), wherein each of the abovesubstituents is optionally substituted by 1, 2, 3 or 4 substitutentsindependently selected from F, Cl, Br, CN, N₃, —OH, —NH₂, C₁-C₃ alkyl,C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃ hydroxyalkyl, C₁-C₃ aminoalkyl andC₁-C₃ alkylamino.

In another embodiment, each R¹⁷ is independently F, Cl, Br, I, CN, NO₂,N₃, —OH, —NH₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄haloalkyl, C₃-C₆ cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6membered heteroaryl, C₁-C₄ aminoalkyl, C₁-C₄ alkylamino, C₁-C₄ alkoxyl,C₁-C₄ hydroxyalkyl, —NH(C₀-C₃ alkylene)-(C₃-C₆ cycloalkyl), —NH(C₀-C₃alkylene)-(4-7 membered heterocyclyl), —N[(C₀-C₃ alkylene)-(C₃-C₆cycloalkyl)]₂, —N[(C₀-C₃ alkylene)-(4-7 membered heterocyclyl)]₂,—O(C₀-C₃ alkylene)-(C₃-C₆ cycloalkyl) or —O(C₀-C₃ alkylene)-(4-7membered heterocyclyl).

In yet another embodiment, some non-limiting examples of the compounddisclosed herein, and their stereoisomer, tautomer, N-oxide, solvate,pharmaceutically acceptable salts and solvates thereof, are shown in thefollowing:

TABLE 2

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(34)

(48)

(49)

Unless otherwise stated, all stereoisomers, tautomers, solvates,metabolites, salts, and pharmaceutically acceptable prodrugs of thecompounds of Formula (I) and Formula (II) are within the scope of theinvention.

The compounds disclosed herein may contain asymmetric or chiral centers,and therefore exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of compounds of Formula (I) and Formula(II), including but not limited to, diastereomers, enantiomers,atropisomers, conformers (rotamers) and geometric (cis/trans) isomers aswell as mixtures thereof such as racemic mixtures, form part of thepresent invention.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

The compounds of Formula (I) and Formula (II) may exist in differenttautomeric forms, and all such forms are embraced within the scope ofthe invention, as defined by the claims.

The compounds of Formula (I) and Formula (II) can be in the form ofsalts. In one embodiment, the salts are pharmaceutically acceptablesalts. The phrase “pharmaceutically acceptable” indicates that thesubstance or composition must be compatible chemically and/ortoxicologically, with the other ingredients comprising a formulation,and/or the mammal being treated therewith. In another embodiment, thesalts are not necessarily pharmaceutically acceptable salts, and whichmay be useful as intermediates for preparing and/or purifying compoundsof Formula (I) and Formula (II) and/or for separating enantiomers ofcompounds of Formula (I) and Formula (II).

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, subsalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, chlorinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable. Lists of additional suitable salts can be found, e.g., in“Remington's Pharmaceutical Sciences”, 20th ed., Mack PublishingCompany, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Furthermore, the compounds disclosed herein, including their salts, canalso be obtained in the form of their hydrates, or include othersolvents such as ethanol, DMSO, and the like, used for theircrystallization. The compounds of the present invention may inherentlyor by design form solvates with pharmaceutically acceptable solvents(including water); therefore, it is intended that the invention embraceboth solvated and unsolvated forms.

Any formula given herein is also intended to represent isotopicallyunenriched forms as well as isotopically enriched forms of thecompounds. Isotopically enriched compounds have structures depicted bythe formulas given herein except that one or more atoms are replaced byan atom having a selected atomic mass or mass number. Examples ofisotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine, and chlorine, such as ²H (deuterium, D), ³H, ¹¹C, ¹³C, ¹⁴C,¹⁵N, ¹⁷O, ¹⁸O, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵I, respectively.

In another aspect, the compounds of the invention include isotopicallyenriched compounds as defined herein, for example those into whichradioactive isotopes, such as ³H, ¹⁴C and ¹⁸F, or those into whichnon-radioactive isotopes, such as ²H and ¹³C are present. Suchisotopically enriched compounds are useful in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F-enriched compound may be particularlydesirable for PET or SPECT studies. Isotopically-enriched compounds ofFormula (I) and Formula (II) can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the accompanying Examples and Preparations usingan appropriate isotopically-labeled reagent in place of the non-labeledreagent previously employed.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of Formula (I) and Formula (II). Theconcentration of such a heavier isotope, specifically deuterium, may bedefined by the isotopic enrichment factor. The term “isotopic enrichmentfactor” as used herein means the ratio between the isotopic abundanceand the natural abundance of a specified isotope. If a substituent in acompound of this invention is denoted deuterium, such compound has anisotopic enrichment factor for each designated deuterium atom of atleast 3500 (52.5% deuterium incorporation at each designated deuteriumatom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5%deuterium incorporation), at least 5000 (75% deuterium incorporation),at least 5500 (82.5% deuterium incorporation), at least 6000 (90%deuterium incorporation), at least 6333.3 (95% deuterium incorporation),at least 6466.7 (97% deuterium incorporation), at least 6600 (99%deuterium incorporation), or at least 6633.3 (99.5% deuteriumincorporation). Pharmaceutically acceptable solvates in accordance withthe invention include those wherein the solvent of crystallization maybe isotopically substituted, e.g. D₂O, acetone-d₆, DMSO-d₆.

In another aspect, provided herein are intermediates for preparing thecompounds disclosed herein.

In another aspect, provided herein are methods of preparing, methods ofseparating, and methods of purifying the compounds disclosed herein.

In another aspect, provided herein is a pharmaceutical compositioncomprising a therapeutically effective amount of the compound disclosedherein, and a pharmaceutically acceptable excipient, carrier, adjuvant,vehicle or a combination thereof. In some embodiments, the compositionis a liquid, solid, semi-solid, gel, or an aerosol form.

In another aspect, provided herein is a method of treating a disease ordisorder modulated by one or more protein kinases such as JAK kinases,FLT3 kinase and Aurora kinases, comprising administering to a mammal inneed of such treatment an effective amount of a compound or apharmaceutical composition disclosed herein. In one embodiment, thedisease or disorder is selected from proliferative disease, autoimmunedisease, allergic disease, inflammatory disease or transplantationrejection.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in the treatment of disease ordisorder selected from proliferative disease, autoimmune disease,allergic disease, inflammatory disease or transplantation rejection.

In another aspect, provided herein is the use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for the treatment of disease or disorder selected fromproliferative disease, autoimmune disease, allergic disease,inflammatory disease or transplantation rejection.

In still another aspect, provided herein is use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for modulating the activity of protein kinase.

Pharmaceutical Composition, Formulations and Administration of theCompounds of the Invention

The present invention provides a pharmaceutical composition that includea compound disclosed herein, or a compound listed in Table 1 and Table2; and a pharmaceutically acceptable excipient, carrier, adjuvant,vehicle or a combination thereof. The amount of compound in thepharmaceutical composition disclosed herein is such that is effective todetectably inhibit a protein kinase in a biological sample or in apatient.

It will also be appreciated that certain compounds disclosed herein canexist in free form for treatment, or where appropriate, as apharmaceutically acceptable derivative thereof. Some non-limitingexamples of pharmaceutically acceptable derivative includepharmaceutically acceptable prodrugs, salts, esters, salts of suchesters, or any other adduct or derivative which upon administration to apatient in need is capable of providing, directly or indirectly, acompound as otherwise described herein, or a metabolite or residuethereof.

The pharmaceutical compositions disclosed herein may be prepared andpackaged in bulk form wherein a safe and effective amount of thecompound disclosed herein can be extracted and then given to the patientsuch as with powders or syrups. Alternatively, the pharmaceuticalcompositions disclosed herein may be prepared and packaged in unitdosage form wherein each physically discrete unit contains the compounddisclosed herein. When prepared in unit dosage form, the pharmaceuticalcompositions of the invention typically may contain, for example, from0.5 mg to 1 g, or from 1 mg to 700 mg, or from 5 mg to 100 mg of thecompound disclosed herein.

As used herein, “pharmaceutically acceptable excipient” means apharmaceutically acceptable material, composition or vehicle involved ingiving form or consistency to the pharmaceutical composition. Eachexcipient must be compatible with the other ingredients of thepharmaceutical composition when commingled such that interactions whichwould substantially reduce the efficacy of the compound disclosed hereinwhen administered to a patient and interactions which would result inpharmaceutical compositions that are not pharmaceutically acceptable areavoided. In addition, each excipient must bepharmaceutically-acceptable, e.g., of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending uponthe particular dosage form chosen. In addition, suitablepharmaceutically acceptable excipients may be chosen for a particularfunction that they may serve in the composition. For example, certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of uniform dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of stable dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the carrying or transporting of the compound or compoundsdisclosed herein once administered to the patient from one organ, orportion of the body, to another organ, or portion of the body. Certainpharmaceutically acceptable excipients may be chosen for their abilityto enhance patient compliance.

Suitable pharmaceutically acceptable excipients comprise the followingtypes of excipients: diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweetners, flavoring agents, flavor masking agents, coloring agents,anticaking agents, hemectants, chelating agents, plasticizers, viscosityincreasing agents, antioxidants, preservatives, stabilizers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchof the excipient is present in the formulation and what other excipientsare present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically-acceptable excipients inappropriate amounts for use in the invention. In addition, there are anumber of resources that are available to the skilled artisan whichdescribe pharmaceutically acceptable excipients and may be useful inselecting suitable pharmaceutically acceptable excipients. Examplesinclude Remington's Pharmaceutical Sciences (Mack Publishing Company),The Handbook of Pharmaceutical Additives (Gower Publishing Limited), andThe Handbook of Pharmaceutical Excipients (the American PharmaceuticalAssociation and the Pharmaceutical Press).

In Remington: The Science and Practice of Pharmacy, 21st edition, 2005,ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, andEncyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C.Boylan, 1988-1999, Marcel Dekker, New York, the contents of each ofwhich is incorporated by reference herein, are disclosed variouscarriers used in formulating pharmaceutically acceptable compositionsand known techniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds disclosedherein, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention.

The pharmaceutical compositions disclosed herein are prepared usingtechniques and methods known to those skilled in the art. Some of themethods commonly used in the art are described in Remington'sPharmaceutical Sciences (Mack Publishing Company).

Accordingly, in another aspect the invention is directed to process forthe preparation of a pharmaceutical composition comprising the compounddisclosed herein and a pharmaceutically acceptable excipient, carrier,adjuvant, vehicle or a combination thereof, which comprises mixing theingredients. A pharmaceutical composition comprising the compounddisclosed herein may be prepared by, for example, admixture at ambienttemperature and atmospheric pressure.

The compounds disclosed herein will typically be formulated into adosage form adapted for administration to the patient by the desiredroute of administration. For example, dosage forms include those adaptedfor (1) oral administration such as tablets, capsules, caplets, pills,troches, powders, syrups, elixers, suspensions, solutions, emulsions,granula, and cachets; (2) parenteral administration such as sterilesolutions, suspensions, and freeze drying powder; (3) transdermaladministration such as transdermal patches; (4) rectal administrationsuch as suppositories; (5) inhalation such as aerosols, solutions, anddry powders; and (6) topical administration such as creams, ointments,lotions, solutions, pastes, sprays, foams, and gels.

In one embodiment, the compounds disclosed herein will be formulated fororal administration. In another embodiment, the compounds disclosedherein will be formulated for inhaled administration. In a furtherembodiment, the compounds disclosed herein will be formulated forintranasal administration. In another embodiment, the compoundsdisclosed herein will be formulated for transdermal administration. In afurther embodiment, the compounds disclosed herein will be formulatedfor topical administration.

The pharmaceutical compositions provided herein can be provided ascompressed tablets, tablet triturates, chewable lozenges, rapidlydissolving tablets, multiple compressed tablets, or enteric-coatingtablets, sugar-coated, or film-coated tablets. Enteric-coated tabletsare compressed tablets coated with substances that resist the action ofstomach acid but dissolve or disintegrate in the intestine, thusprotecting the active ingredients from the acidic environment of thestomach. Enteric-coatings include, but are not limited to, fatty acids,fats, phenyl salicylate, waxes, shellac, ammoniated shellac, andcellulose acetate phthalates. Sugar-coated tablets are compressedtablets surrounded by a sugar coating, which may be beneficial incovering up objectionable tastes or odors and in protecting the tabletsfrom oxidation. Film-coated tablets are compressed tablets that arecovered with a thin layer or film of a water-soluble material. Filmcoatings include, but are not limited to, hydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol 4000, and cellulose acetatephthalate. Film coating imparts the same general characteristics assugar coating. Multiple compressed tablets are compressed tablets madeby more than one compression cycle, including layered tablets, andpress-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein can be provided as softor hard capsules, which can be made from gelatin, methylcellulose,starch, or calcium alginate. The hard gelatin capsule, also known as thedry-filled capsule (DFC), consists of two sections, one slipping overthe other, thus completely enclosing the active ingredient. The softelastic capsule (SEC) is a soft, globular shell, such as a gelatinshell, which is plasticized by the addition of glycerin, sorbitol, or asimilar polyol. The soft gelatin shells may contain a preservative toprevent the growth of microorganisms. Suitable preservatives are thoseas described herein, including methyl- and propyl-parabens, and sorbicacid. The liquid, semisolid, and solid dosage forms provided herein maybe encapsulated in a capsule. Suitable liquid and semisolid dosage formsinclude solutions and suspensions in propylene carbonate, vegetableoils, or triglycerides. Capsules containing such solutions can beprepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and4,410,545. The capsules may also be coated as known by those of skill inthe art in order to modify or sustain dissolution of the activeingredient.

The pharmaceutical compositions provided herein can be provided inliquid and semisolid dosage forms, including emulsions, solutions,suspensions, elixirs, and syrups. An emulsion is a two-phase system, inwhich one liquid is dispersed in the form of small globules throughoutanother liquid, which can be oil-in-water or water-in-oil. Emulsions mayinclude a pharmaceutically acceptable nonaqueous liquid or solvent,emulsifying agent, and preservative. Suspensions may include apharmaceutically acceptable suspending agent and preservative. Aqueousalcoholic solutions may include a pharmaceutically acceptable acetal,such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g.,acetaldehyde diethyl acetal; and a water-miscible solvent having one ormore hydroxyl groups, such as propylene glycol and ethanol. Elixirs areclear, sweetened, and hydroalcoholic solutions. Syrups are concentratedaqueous solutions of a sugar, for example, sucrose, and may also containa preservative. For a liquid dosage form, for example, a solution in apolyethylene glycol may be diluted with a sufficient quantity of apharmaceutically acceptable liquid carrier, e.g., water, to be measuredconveniently for administration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations can further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The composition can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The pharmaceutical compositions provided herein for oral administrationcan be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein can be provided asnon-effervescent or effervescent, granules and powders, to bereconstituted into a liquid dosage form. Pharmaceutically acceptablecarriers and excipients used in the non-effervescent granules or powdersmay include diluents, sweeteners, and wetting agents. Pharmaceuticallyacceptable carriers and excipients used in the effervescent granules orpowders may include organic acids and a source of carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The compounds disclosed herein may also be coupled with soluble polymersas targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compoundsdisclosed herein may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

The pharmaceutical compositions provided herein can be formulated asimmediate or modified release dosage forms, including delayed-,sustained-, pulsed-, controlled-, targeted-, and programmed-releaseforms.

The pharmaceutical compositions provided herein can be co-formulatedwith other active ingredients which do not impair the desiredtherapeutic action, or with substances that supplement the desiredaction.

The pharmaceutical compositions provided herein can be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, intravesical, and subcutaneousadministration.

The pharmaceutical compositions provided herein can be formulated in anydosage forms that are suitable for parenteral administration, includingsolutions, suspensions, emulsions, micelles, liposomes, microspheres,nanosystems, and solid forms suitable for solutions or suspensions inliquid prior to injection. Such dosage forms can be prepared accordingto conventional methods known to those skilled in the art ofpharmaceutical science (see, Remington: The Science and Practice ofPharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationcan include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Non-aqueous vehicles include, but are not limited to, fixed oils ofvegetable origin, castor oil, corn oil, cottonseed oil, olive oil,peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Water-miscible vehiclesinclude, but are not limited to, ethanol, 1,3-butanediol, liquidpolyethylene glycol (e.g., polyethylene glycol 300 and polyethyleneglycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone,N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsinclude those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-P-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-P-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

The pharmaceutical compositions provided herein can be formulated forsingle or multiple dosage administration. The single dosage formulationsare packaged in an ampoule, a vial, or a syringe. The multiple dosageparenteral formulations must contain an antimicrobial agent atbacteriostatic or fungistatic concentrations. All parenteralformulations must be sterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions are provided asready-to-use sterile solutions. In another embodiment, thepharmaceutical compositions are provided as sterile dry solubleproducts, including lyophilized powders and hypodermic tablets, to bereconstituted with a vehicle prior to use. In yet another embodiment,the pharmaceutical compositions are provided as ready-to-use sterilesuspensions. In yet another embodiment, the pharmaceutical compositionsare provided as sterile dry insoluble products to be reconstituted witha vehicle prior to use. In still another embodiment, the pharmaceuticalcompositions are provided as ready-to-use sterile emulsions.

The pharmaceutical compositions can be formulated as a suspension,solid, semi-solid, or thixotropic liquid, for administration as animplanted depot. In one embodiment, the pharmaceutical compositionsprovided herein are dispersed in a solid inner matrix, which issurrounded by an outer polymeric membrane that is insoluble in bodyfluids but allows the active ingredient in the pharmaceuticalcompositions diffuse through.

Suitable inner matrixes include polymethylmethacrylate,polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethylene terephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinyl acetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers, such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinyl alcohol, and cross-linked partiallyhydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinyl chloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer.

In another aspect, the pharmaceutical compositions disclosed herein canbe formulated in any dosage forms that are adapted for administration toa patient by inhalation, for example as a dry powder, an aerosol, asuspension, or a solution composition. In one embodiment, thepharmaceutical compositions disclosed herein can be formulated in adosage form adapted for administration to a patient by inhalation as adry powder. In a further embodiment, the pharmaceutical compositionsdisclosed herein can be formulated in a dosage form adapted foradministration to a patient by inhalation via a nebulizer. Dry powdercompositions for delivery to the lung by inhalation typically comprisethe compounds disclosed herein as a finely divided powder together withone or more pharmaceutically-acceptable excipients as finely dividedpowders. Pharmaceutically-acceptable excipients particularly suited foruse in dry powders are known to those skilled in the art and includelactose, starch, mannitol, and mono-, di-, and polysaccharides. Thefinely divided powder may be prepared by, for example, micronisation andmilling. Generally, the size-reduced (eg micronised) compound can bedefined by a D₅₀ value of about 1 to about 10 microns (for example asmeasured using laser diffraction).

Aerosols may be formed by suspending or dissolving the compounddisclosed herein in a liquified propellant. Suitable propellants includehalocarbons, hydrocarbons, and other liquified gases. Representativepropellants include: trichlorofluoromethane (propellant 11),dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane(propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoroethane(HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12),heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane,perfluoropentane, butane, isobutane, and pentane. Aerosols comprisingthe compound disclosed herein will typically be administered to apatient via a metered dose inhaler (MDI). Such devices are known tothose skilled in the art.

The aerosol may contain additional pharmaceutically-acceptableexcipients typically used with MDIs such as surfactants, lubricants,cosolvents and other excipients to improve the physical stability of theformulation, to improve valve performance, to improve solubility, or toimprove taste.

Pharmaceutical compositions adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the patient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 1986,3(6), 318.

Pharmaceutical compositions adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils. Ointments, creams andgels, may, for example, be formulated with an aqueous or oily base withthe addition of suitable thickening and/or gelling agent and/orsolvents. Such bases may thus, for example, include water and/or oilsuch as liquid paraffin or a vegetable oil such as arachis oil or castoroil, or a solvent such as polyethylene glycol. Thickening agents andgelling agents which may be used according to the nature of the baseinclude soft paraffin, aluminium stearate, cetostearyl alcohol,polyethylene glycols, woolfat, beeswax, carboxypolymethylene andcellulose derivatives, and/or glyceryl monostearate and/or non-ionicemulsifying agents.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of anysuitable powder base, for example, talc, lactose or starch. Drops may beformulated with an aqueous or nonaqueous base also comprising one ormore dispersing agents, solubilizing agents, suspending agents orpreservatives.

Topical preparations may be administered by one or more applications perday to the affected area; over skin areas occlusive dressings mayadvantageously be used. Continuous or prolonged delivery may be achievedby an adhesive reservoir system.

For treatments of the eye or other external tissues, for example mouthand skin, the compositions may be applied as a topical ointment orcream. When formulated in an ointment, the compound disclosed herein maybe employed with either a paraffinic or a water-miscible ointment base.Alternatively, the compound disclosed herein may be formulated in acream with an oil-in-water cream base or a water-in-oil base.

Use of the Compounds and Compositions of the Invention

The present invention provides a method of using a compound disclosedherein, or a pharmaceutical composition comprising the compounddisclosed herein for the treatment, prevention, or amelioration of adisease or disorder that is mediated or otherwise affected via one ormore protein kinases activity, such as JAK kinases (including JAK1,JAK2, JAK3 or TYK2 kinase), FLT3 kinase, and Aurora kinases (includingAurora-A, Aurora-B and Aurora-C) activity or one or more symptoms ofdiseases or disorders that are mediated or otherwise affected via one ormore protein kinases activity, such as JAK kinases (including JAK1,JAK2, JAK3 or TYK2 kinase), FLT3 kinase and Aurora kinases (includingAurora-A, Aurora-B and Aurora-C kinase) activity.

FLT3 kinase can be wild type and/or mutant form of FLT3 kinase.

JAK kinases can be wild type and/or mutant form of JAK1, JAK2, JAK3 orTYK2 kinase.

In one embodiment, provided herein is a method of using a compounddisclosed herein or a pharmaceutical composition comprising a compounddisclosed herein for the treatment, prevention, or amelioration of adisease or disorder that is mediated or otherwise affected viainappropriate JAK1 kinase activity or one or more symptoms of diseasesor disorders that are mediated or otherwise affected via inappropriateJAK1 kinase activity. In another embodiment, a disease, a disorder orone or more symptoms of diseases or disorders is related to theinappropriate activity of JAK2 kinase. In yet another embodiment, adisease, a disorder or one or more symptoms of diseases or disorders isrelated to the inappropriate activity of JAK3 kinase.

In one embodiment, provided herein is a method of using a compounddisclosed herein or a pharmaceutical composition comprising a compounddisclosed herein for the treatment, prevention, or amelioration of adisease or disorder that is mediated or otherwise affected viainappropriate FLT3 kinase activity or one or more symptoms of diseasesor disorders that are mediated or otherwise affected via inappropriateFLT3 kinase activity.

In one embodiment, provided herein is a method of using a compounddisclosed herein or a pharmaceutical composition comprising a compounddisclosed herein for the treatment, prevention, or amelioration of adisease or disorder that is mediated or otherwise affected viainappropriate Aurora-A kinase activity or one or more symptoms ofdiseases or disorders that are mediated or otherwise affected viainappropriate Aurora-A kinase activity. In another embodiment, adisease, a disorder or one or more symptoms of diseases or disorders isrelated to the inappropriate activity of Aurora-B kinase. In yet anotherembodiment, a disease, a disorder or one or more symptoms of diseases ordisorders is related to the inappropriate activity of Aurora-C kinase.

“Inappropriate JAK kinase activity” refers to any JAK kinase activitythat deviates from the normal JAK kinase activity expected in aparticular patient. Inappropriate JAK kinase may take the form of, forinstance, an abnormal increase in activity, or an aberration in thetiming and or control of JAK kinase activity. Such inappropriateactivity may result then, for example, from overexpression or mutationof the protein kinase leading to inappropriate or uncontrolledactivation. Accordingly, in another aspect the invention is directed tomethods of treating such diseases and disorders.

Consistent with the description above, such diseases or disordersinclude without limitation: myeloproliferative disorders such aspolycythemia vera (PCV), essential thrombocythemia and idiopathicmyelofibrosis (IMF); leukemia such as myeloid leukemia including chronicmyeloid leukemia (CML), imatinib-resistant forms of CML, acute myeloidleukemia (AML), and a subtype of AML, acute megakaryoblastic leukemia(AMKL); lymphoproliferative diseases such as acute lymphocytic leukemia(ALL) and myeloma; cancer including head and neck cancer, prostatecancer, breast cancer, ovarian cancer, melanoma, lung cancer, braintumor, pancreatic cancer and renal carcinoma; and allergic orinflammatory diseases or disorders related to immune dysfunction,immunodeficiency, immunomodulation, autoimmune diseases, transplantationrejection, graft-versus-host disease, wound healing, kidney disease,multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis,psoriasis, allergic rhinitis, inflammatory bowel disease includingCrohn's disease and ulcerative colitis (UC), systemic lupuserythematosis (SLE), arthritis, osteoarthritis, rheumatoid arthritis,osteoporosis, asthma and chronic obstructive pulmonary disease (COPD)and dry eye syndrome (or keratoconjunctivitis sicca (KCS)).

In one aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for preventing and/or treatingproliferative disease, autoimmune disease, allergic disease,inflammatory disease or transplantation rejection in mammals includinghumans.

In yet another aspect, provided herein is a method of treating a mammalhaving, or at risk of having a disease or disclosed herein, said methodcomprising administering an effective condition-treating orcondition-preventing amount of one or more of the pharmaceuticalcompositions or the compounds disclosed herein. In a particular aspect,provided here is a method of treating a mammal having, or at risk ofhaving proliferative disease, autoimmune disease, allergic disease,inflammatory disease or transplantation rejection.

In additional method of treatment aspects, provided herein is a methodof treatment and/or prophylaxis of a mammal susceptible to or afflictedwith a proliferative disease, said methods comprising administering aneffective condition-treating or condition-preventing amount of one ormore of the pharmaceutical compositions or compounds disclosed herein.In a specific embodiment, the proliferative disease is selected fromcancer (e.g. solid tumors such as uterine leiomyosarcoma or prostatecancer), polycythemia vera, essential thrombocytosis, myelofibrosis,leukemia (e.g. AML, CML, ALL or CLL), and multiple myeloma.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in the treatment, and/orprophylaxis of a proliferative disease. In a specific embodiment, theproliferative disease is selected from cancer (e.g. solid tumors such asuterine leiomyosarcoma or prostate cancer), polycythemia vera, essentialthrombocytosis, myelofibrosis, leukemia (e.g. AML, CML, ALL or CLL), andmultiple myeloma.

In yet another aspect, provided herein is the use of the compound or thepharmaceutical composition disclosed herein for use in the manufactureof a medicament for the treatment, and/or prophylaxis of a proliferativedisease. In a specific embodiment, the proliferative disease is selectedfrom cancer (e.g. solid tumors such as uterine leiomyosarcoma orprostate cancer), polycythemia vera, essential thrombocytosis,myelofibrosis, leukemia (e.g. AML, CML, ALL or CLL), and multiplemyeloma.

In another aspect, provided herein is a method of treatment and/orprophylaxis of a mammal susceptible to or afflicted with an autoimmunedisease. The methods comprise administering an effectivecondition-treating or condition-preventing amount of one or more of thepharmaceutical compositions or compounds disclosed herein. In a specificembodiment, the autoimmune disease is selected from COPD, asthma,systemic and cutaneous lupus erythematosis, lupus nephritis,dermatomyositis, Sjogren's syndrome, psoriasis and type I diabetesmellitus.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in the treatment, and/orprophylaxis of an autoimmune disease. In a specific embodiment, theautoimmune disease is selected from COPD, asthma, systemic and cutaneouslupus erythematosis, lupus nephritis, dermatomyositis, Sjogren'ssyndrome, psoriasis and type I diabetes mellitus.

In yet another aspect, provided here is the use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for the treatment, and/or prophylaxis of an autoimmunedisease. In a specific embodiment, the autoimmune disease is selectedfrom COPD, asthma, systemic and cutaneous lupus erythematosis, lupusnephritis, dermatomyositis, Sjogren's syndrome, psoriasis and type Idiabetes mellitus.

In a method of treatment aspects, provided herein are methods oftreatment and/or prophylaxis of a mammal susceptible to or afflictedwith an allergic disease. The methods comprising administering aneffective condition-treating or condition-preventing amount of one ormore of the pharmaceutical compositions or the compounds disclosedherein. In a specific embodiment, the allergic disease is selected fromallergic airway disease, sinusitis, eczema and hives, food allergies andallergies to insect venom.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in the treatment, and/orprophylaxis of an allergic disease. In a specific embodiment, theallergic disease is selected from allergic airway disease, sinusitis,eczema and hives, food allergies and allergies to insect venom.

In yet another aspect, provided herein is the use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for the treatment, or prophylaxis of an allergic disease. Ina specific embodiment, the allergic disease is selected from allergicairway disease, sinusitis, eczema and hives, food allergies andallergies to insect venom.

In another aspect, provided herein are methods of treatment and/orprophylaxis of a mammal susceptible to or afflicted with an inflammatorydisease. The methods comprise administering an effectivecondition-treating or condition-preventing amount of one or more of thepharmaceutical compositions or the compounds disclosed herein. In aspecific embodiment, the inflammatory disease is selected frominflammatory bowel syndrome, Crohn's disease, rheumatoid arthritis,juvenile arthritis and psoriatic arthritis.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in the treatment, and/orprophylaxis of an inflammatory disease. In a specific embodiment, theinflammatory disease is selected from inflammatory bowel syndrome,Crohn's disease, rheumatoid arthritis, juvenile arthritis and psoriaticarthritis.

In yet another aspect, provided herein is the use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for the treatment, and/or prophylaxis of an inflammatorydisease. In a specific embodiment, the inflammatory disease is selectedfrom inflammatory bowel syndrome, Crohn's disease, rheumatoid arthritis,juvenile arthritis and psoriatic arthritis.

In another aspect, provided herein are methods of treatment and/orprophylaxis of a mammal susceptible to or afflicted with transplantationrejection. The methods comprising administering an effectivecondition-treating or condition-preventing amount of one or more of thepharmaceutical compositions or the compound of the invention hereindescribed. In a specific embodiment, the transplantation rejection isorgan transplant rejection, tissue transplant rejection and celltransplant rejection.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in the treatment, and/orprophylaxis of transplantation rejection. In a specific embodiment, thetransplantation rejection is organ transplant rejection, tissuetransplant rejection and cell transplant rejection.

In yet another aspect, provided herein is the use of the compound or thepharmaceutical composition disclosed herein for use in the manufactureof a medicament for the treatment and/or prophylaxis of transplantationrejection. In a specific embodiment, the transplantation rejection isorgan transplant rejection, tissue transplant rejection and celltransplant rejection.

The present invention provides the compound or the pharmaceuticalcomposition disclosed herein for use as a pharmaceutical especially inthe treatment and/or prophylaxis of the aforementioned diseases ordisorders. Also provided herein is the use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for the treatment and/or prophylaxis of one of theaforementioned diseases or disorders.

A particular regimen of the present method comprises the administrationto a subject suffering from a disease involving inflammation, of aneffective amount of a compound disclosed herein for a period of timesufficient to reduce the level of inflammation in the subject, andpreferably terminate the processes responsible for said inflammation. Aspecial embodiment of the method comprises administering of an effectiveamount of a compound disclosed herein to a subject patient sufferingfrom or susceptible to the development of rheumatoid arthritis, for aperiod of time sufficient to reduce or prevent, respectively,inflammation in the joints of said patient, and preferably terminate,the processes responsible for said inflammation.

A further particular regimen of the present method comprises theadministration to a subject suffering from a disease involvingproliferative disease, of an effective amount of a compound disclosedherein for a period of time sufficient to reduce the level ofproliferative disease in the subject, and preferably terminate theprocesses responsible for said proliferative disease. A particularembodiment of the method comprises administering of an effective amountof a compound disclosed herein to a subject patient suffering from orsusceptible to the development of cancer, for a period of timesufficient to reduce or prevent, respectively, solid tumor of saidpatient, and preferably terminate, the processes responsible for saidsolid.

Combination Therapy

A compound disclosed herein can be administered as the sole active agentor it can be administered in combination with other therapeutic agents,including other compounds that demonstrate the same or a similartherapeutic activity and that are determined to be safe and efficaciousfor such combined administration.

In one aspect, provided herein is a method of treating, preventing,managing, or ameliorating a disease or disorder comprising administeringa safe and effective amount of a combination comprising the compounddisclosed herein together with one or more therapeutically activeagents. In one embodiment, the combinations comprising one or two othertherapeutic agents.

Example of other therapeutic agents may include without limitationanti-cancer agents, including chemotherapeutic agents andantiproliferative agents; anti-inflammatory agents and immunomodulatoryagents or immunosuppressive agents.

In another aspect, provided herein is a product comprising a compounddisclosed herein and at least one other therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use in therapy. Inone embodiment, the therapy is the treatment of a disease or disordermediated by the activity of one or more protein kinases activity, suchas JAK kinases, FLT3 kinase and Aurora kinases. Products provided as acombined preparation include a composition comprising the compounddisclosed herein and the other therapeutic agent(s) together in the samepharmaceutical composition, or the compound disclosed herein and theother therapeutic agent(s) in separate form, e.g. in the form of a kit.

In another aspect, provided herein is a pharmaceutical compositioncomprising a compound disclosed herein and another therapeutic agent(s).In one embodiment, the pharmaceutical composition may comprise apharmaceutically acceptable excipient, carrier, adjuvant or vehicle asdescribed above.

In another aspect, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound disclosed herein. In one embodiment, the kit comprises meansfor separately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

The invention also provides the use of a compound disclosed herein fortreating a disease or condition mediated by the activity of one or moreprotein kinases, such as JAK kinases, FLT3 kinase and Aurora kinases,wherein the patient has previously (e.g. within 24 hours) been treatedwith another therapeutic agent. The invention also provides the use ofanother therapeutic agent for treating a disease or condition mediatedby the activity of one or more protein kinases, such as JAK kinases,FLT3 kinase and Aurora kinases, wherein the patient has previously (e.g.within 24 hours) been treated with a compound disclosed herein.

The compounds disclosed herein may be administered as the sole activeingredient or in conjunction with, e.g. as an adjuvant to, othertherapeutic agent.

In one embodiment, other therapeutic agent refers to chemotherapeuticagents or antiproliferative agents. Some non-limiting examples of knownchemotherapeutic agents include other therapies or anticancer agentsthat may be used in combination with the inventive anticancer agents ofthe present invention and include surgery, radiotherapy (in but a fewexamples, gamma radiation, neutron beam radiotherapy, electron beamradiotherapy, proton therapy, brachytherapy, and systemic radioactiveisotopes, to name a few), endocrine therapy, taxanes (taxol, taxotereetc), platinum derivatives (cisplatin, carboplatin), biologic responsemodifiers (interferons, interleukins), tumor necrosis factor (TNF, TRAILreceptor targeting agents, to name a few), hyperthermia and cryotherapy,agents to attenuate any adverse effects (e.g., antiemetics), and otherapproved chemotherapeutic drugs, including, but not limited to,alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide,melphalan, ifosfamide), antimetabolites (methotrexate, pemetrexed etc),purine antagonists and pyrimidine antagonists (6-mercaptopurine,5-fluorouracil, cytarabile, gemcitabine), spindle poisons (vinblastine,vincristine, vinorelbine), podophyllotoxins (etoposide, irinotecan,topotecan), antibiotics (doxorubicin, bleomycin, mitomycin),nitrosoureas (carmustine, lomustine), cell cycle inhibitors (KSP mitotickinesin inhibitors, CENP-E and CDK inhibitors), enzymes (asparaginase),hormones (tamoxifen, leuprolide, flutamide, megestrol, dexamethasone),antiangiogenic agents (avastin and others), monoclonal antibodies(BENLYSTA®), brentuximab (ADCETRIS®), cetuximab (ERBITUX®), gemtuzumab(MYLOTARG®), ipilimumab (YERVOY®), ofatumumab (ARZERRA®), panitumumab(VECTIBIX®), ranibizumab (LUCERTIS®), rituximab (RITUXAN®), tositumomab(BEXXAR®), trastuzumab (HERCEPTIN®)), kinase inhibitors (imatinib(GLEEVEC®), sunitinib (SUTENT®), sorafenib (NEXAVAR®), erlotinib,(TARCEVA®), gefitinib (IRESSA®), dasatinib (SPRYCEL®), nilotinib(TASIGNA®), lapatinib (TYKERB®), crizotinib (XALKORI®), ruxolitinib(JAKAFI®), vemurafenib (ZELBORAF®), vandetanib (CAPRELSA®), pazopanib(VOTRIENT®), and others), and agents inhibiting or activating cancerpathways such as the mTOR, HIF (hypoxia induced factor) pathways (suchas everolimus and temsirolimus) and others. For a more comprehensivediscussion of updated cancer therapies see, http://www.nci.nih.gov/, alist of the FDA approved oncology drugs athttp://www.fda.gov/cder/cancer/druglist-rame.htm, and The Merck Manual,Eighteenth Ed. 2006, all of which are herein incorporated by referencein their entireties. In another embodiment, the compounds of the presentinvention can be combined, with cytotoxic anti-cancer agents. Examplesof such agents can be found in the 13th Edition of the Merck Index(2001). These agents include, by no way of limitation, asparaginase,bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin,doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil,hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin,lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate,mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine,raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine,vincristine and vindesine. Other cytotoxic drugs suitable for use withthe compounds of the invention include, but are not limited to, thosecompounds acknowledged to be used in the treatment of neoplasticdiseases, such as those for example in Goodman and Gilman's ThePharmacological Basis of Therapeutics (Ninth Edition, 1996,McGraw-Hill). These agents include, by no way of limitation,aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidinecladribine, busulfan, diethylstilbestrol, 2,2′-difluorodeoxycytidine,docetaxel, erythrohydroxynonyladenine, ethinyl estradiol,5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabinephosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate,idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate,melphalan, mitotane, paclitaxel, pentostatin,N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide,testosterone propionate, thiotepa, trimethylmelamine, uridine, andvinorelbine.

Other cytotoxic anti-cancer agents suitable for use in combination withthe compounds of the invention also include newly discovered cytotoxicprinciples such as oxaliplatin, vemurafenib, capecitabine, epothiloneand its natural or synthetic derivatives, temozolomide (Quinn et al., J.Clin. Oncol., 2003, 21(4), 646-651), tositumomab (BEXXAR®), trabedectin(Vidal et al., Proceedings of the American Society for ClinicalOncology, 2004, 23, abstract 3181), and the inhibitors of the kinesinspindle protein Eg5 (Wood et al., Curr. Opin. Pharmacol., 2001, 1,370-377).

In another embodiment, the compounds of the present invention can becombined with other signal transduction inhibitors. EGFR family as oneof the target signal transduction inhibitors, such as EGFR, HER-2 andHER-4 (Raymond et al., Drugs, 2000, 60 (Suppl.1), 15-23; Harari et al.,Oncogene, 2000, 19 (53), 6102-6114) and ligands thereof. Examples ofsuch therapies also include, by no way of limitation, small-moleculekinase inhibitors such as imatinib (GLEEVEC®), sunitinib (SUTENT®),sorafenib (NEXAVAR®), erlotinib (TARCEVA®), gefitinib (IRESSA®),dasatinib (SPRYCEL®), nilotinib (TASIGNA®), lapatinib (TYKERB®),crizotinib (XALKORI®), ruxolitinib (JAKAFI®), vemurafenib (ZELBORAF®),vandetanib (CAPRELSA®), pazopanib (VOTRIENT®), afatinib, alisertib,amuvatinib, axitinib, bosutinib, brivanib, canertinib, cabozantinib,cediranib, crenolanib, dabrafenib, dacomitinib, danusertib, dovitinib,foretinib, ganetespib, ibrutinib, iniparib, lenvatinib, linifanib,linsitinib, masitinib, momelotinib, motesanib, neratinib, niraparib,oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib,rigosertib, rucaparib, saracatinib, saridegib, tandutinib, tasocitinib,telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vatalanib,veliparib, vismodegib, volasertib, BMS-540215, BMS777607, JNJ38877605,TKI258, GDC-0941 (Folkes et al. J. Med. Chem. 2008, 51: 5522), BZE235,and others.

In one embodiment, the compounds disclosed herein may be administered inconjunction with, e.g. as an adjuvant to, other drugs e.g.immunosuppressive or immunomodulating agents or other anti-inflammatoryagents, e.g. for the treatment or prevention of alio- or xenograft acuteor chronic rejection or inflammatory or autoimmune disorders, or achemotherapeutic agent, e.g a malignant cell anti-proliferative agent.For example, the compounds disclosed herein may be used in combinationwith a calcineurin inhibitor, e.g. cyclosporin A or FK 506; a mTORinhibitor, e.g. rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, CCI779,ABT578, AP23573, TAFA-93, biolimus-7 or biolimus-9; an ascomycin havingimmuno-suppressive properties, e.g. ABT-281, ASM981, etc.;corticosteroids; cyclophosphamide; azathioprene; methotrexate;leflunomide; mizoribine; mycophenolic acid or salt; mycophenolatemofetil; 15-deoxyspergualine or an immunosuppressive homologue, analogueor derivative thereof, a PKC inhibitor, e.g. as disclosed in WO 02/38561or WO 03/82859, e.g. the compound of Example 56 or 70; immunosuppressivemonoclonal antibodies, e.g., monoclonal antibodies to leukocytereceptors, e.g., MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45,CD52, CD58, CD80, CD86 or their ligands; other immunomodulatorycompounds, e.g. a recombinant binding molecule having at least a portionof the extracellular domain of CTLA4 or a mutant thereof, e.g. an atleast extracellular portion of CTLA4 or a mutant thereof joined to anon-CTLA4 protein sequence, e.g. CTLA4lg (for ex. designated ATCC 68629)or a mutant thereof, e.g. LEA29Y; adhesion molecule inhibitors, e.g.LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4antagonists; or antihistamines; or antitussives, or a bronchodilatoryagent; or an angiotensin receptor blockers; or an anti-infectious agent.

Where the compounds disclosed herein are administered in conjunctionwith other immunosuppressive/immunomodulatory, anti-inflammatory,chemotherapeutic or anti-infectious therapy, dosages of theco-administered immunosuppressant, immunomodulatory, anti-inflammatory,chemotherapeutic or anti-infectious compound will of course varydepending on the type of co-drug employed, e.g. whether it is a steroidor a calcineurin inhibitor, on the specific drug employed, on thecondition being treated and so forth.

In one aspect, provided herein is a combination comprising a compounddisclosed herein together with a β₂-adrenoreceptor agonist. Examples ofβ₂-adrenoreceptor agonists include salmeterol, salbutamol, formoterol,salmefamol, fenoterol, carmoterol, etanterol, naminterol, clenbuterol,pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol,terbutaline and salts thereof, for example the xinafoate(1-hydroxy-2-naphthalenecarboxylate) salt of salmeterol, the sulphatesalt or free base of salbutamol or the fumarate salt of formoterol. Inone embodiment, long-acting β₂-adrenoreceptor agonists, for example,compounds which provide effective bronchodilation for about 12 h orlonger, are preferred.

The β₂-adrenoreceptor agonist may be in the form of a salt formed with apharmaceutically acceptable acid selected from sulphuric, hydrochloric,fumaric, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic),cinnamic, substituted cinnamic, triphenylacetic, sulphamic, sulphanilic,naphthaleneacrylic, benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic,4-chlorobenzoic and 4-phenylbenzoic acid.

In another aspect, provided herein is a combination comprising acompound disclosed herein together with corticosteroids. Suitablecorticosteroids refer to those oral and inhaled corticosteroids andtheir pro-drugs which have anti-inflammatory activity. Examples includemethyl prednisolone, prednisolone, dexamethasone, fluticasonepropionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester (fluticasone furoate),6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl) ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioicacid S-cyanomethyl ester and6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-(1-ethycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester, beclomethasone esters (for example the17-propionate ester or the 17,21-dipropionate ester), budesonide,flunisolide, mometasone esters (for example mometasone furoate),triamcinolone acetonide, rofleponide, ciclesonide(16α,17-[[(cis)-cyclohexylmethylene]bis(oxy)]-11β,21-dihydroxy-pregna-1,4-diene-3,20-dione),butixocort propionate, RPR-106541, and ST-126. Preferred corticosteroidsinclude fluticasone propionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioicacid S-cyanomethyl ester and6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-(1-methylcyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioic acidS-fluoromethyl ester. In one embodiment the corticosteroid is6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.

In another aspect, provided herein is a combination comprising acompound disclosed herein together with non-steroidal GR agonist.Non-steroidal compounds having glucocorticoid agonism that may possessselectivity for transrepression over transactivation and that may beuseful in combination therapy include those covered in the followingpatents: WO 03/082827, WO 98/54159, WO 04/005229, WO 04/009017, WO04/018429, WO 03/104195, WO 03/082787, WO 03/082280, WO 03/059899, WO03/101932, WO 02/02565, WO 01/16128, WO 00/66590, WO 03/086294, WO04/026248, WO 03/061651 and WO 03/08277. Further non-steroidal compoundsare covered in: WO 2006/000401, WO 2006/000398 and WO 2006/015870.

In another aspect, provided herein is a combination comprising acompound disclosed herein together with non-steroidal anti-inflammatorydrugs (NSAID's). Examples of NSAID's include sodium cromoglycate,nedocromil sodium, phosphodiesterase (PDE) inhibitors (for example,theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors),leukotriene antagonists, inhibitors of leukotriene synthesis (forexample montelukast), iNOS inhibitors, tryptase and elastase inhibitors,beta-2 integrin antagonists and adenosine receptor agonists orantagonists (e.g. adenosine 2a agonists), cytokine antagonists (forexample chemokine antagonists, such as a CCR3 antagonist) or inhibitorsof cytokine synthesis, or 5-lipoxygenase inhibitors. An iNOS (induciblenitric oxide synthase inhibitor) is preferably for oral administration.Examples of iNOS inhibitors include those disclosed in WO 93/13055, WO98/30537, WO 02/50021, WO 95/34534 and WO 99/62875. Examples of CCR3inhibitors include those disclosed in WO 02/26722.

In one embodiment, the invention provides the use of the compoundsdisclosed herein in combination with a phosphodiesterase 4 (PDE4)inhibitor, especially in the case of a formulation adapted forinhalation. The PDE4-specific inhibitor useful in this aspect of theinvention may be any compound that is known to inhibit the PDE4 enzymeor which is discovered to act as a PDE4 inhibitor, and which are onlyPDE4 inhibitors, not compounds which inhibit other members of the PDEfamily, such as PDE3 and PDE5, as well as PDE4. Compounds includecis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-oneandcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol].Also,cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid (also known as cilomilast) and its salts, esters, pro-drugs orphysical forms, which is described in U.S. Pat. No. 5,552,438 issued 3Sep. 1996; this patent and the compounds it discloses are incorporatedherein in full by reference.

In another aspect, provided herein is a combination comprising acompound disclosed herein together with an anticholinergic agent.Examples of anticholinergic agents are those compounds that act asantagonists at the muscarinic receptors, in particular those compoundswhich are antagonists of the M₁ or M₃ receptors, dual antagonists of theM₁/M₃ or M₂/M₃, receptors or pan-antagonists of the M₁/M₂/M₃ receptors.Exemplary compounds for administration via inhalation includeipratropium (for example, as the bromide, CAS 22254-24-6, sold under thename ATROVENT®), oxitropium (for example, as the bromide, CAS30286-75-0) and tiotropium (for example, as the bromide, CAS136310-93-5, sold under the name SPIRIVA®). Also of interest arerevatropate (for example, as the hydrobromide, CAS 262586-79-8) andLAS-34273 which is disclosed in WO 01/04118. Exemplary compounds fororal administration include pirenzepine (CAS 28797-61-7), darifenacin(CAS 133099-04-4, or CAS 133099-07-7 for the hydrobromide sold under thename ENABLEX®), oxybutynin (CAS 5633-20-5, sold under the nameDITROPAN®), terodiline (CAS 15793-40-5), tolterodine (CAS 124937-51-5,or CAS 124937-52-6 for the tartrate, sold under the name DETROL®),otilonium (for example, as the bromide, CAS 26095-59-0, sold under thename SPASMOMEN®), trospium chloride (CAS 10405-02-4) and solifenacin(CAS 242478-37-1, or CAS 242478-38-2 for the succinate also known asYM-905 and sold under the name VESICARE®).

In another aspect, provided herein is a combination comprising acompound disclosed herein together with an H1 antagonist. Examples of H1antagonists include, without limitation, amelexanox, astemizole,azatadine, azelastine, acrivastine, brompheniramine, cetirizine,levocetirizine, efletirizine, chlorpheniramine, clemastine, cyclizine,carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine,doxylamine, dimethindene, ebastine, epinastine, efletirizine,fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine,mizolastine, mequitazine, mianserin, noberastine, meclizine,norastemizole, olopatadine, picumast, pyrilamine, promethazine,terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine,particularly cetirizine, levocetirizine, efletirizine and fexofenadine.In a further embodiment the invention provides a combination comprisinga compound disclosed herein together with an H3 antagonist (and/orinverse agonist). Examples of H3 antagonists include, for example, thosecompounds disclosed in WO 2004/035556 and in WO 2006/045416. Otherhistamine receptor antagonists which may be used in combination with thecompounds disclosed herein include antagonists (and/or inverse agonists)of the H4 receptor, for example, the compounds disclosed in Jablonowskiet al., J. Med. Chem., 2003, 46:3957-3960.

In still another aspect, provided herein is a combination comprising acompound disclosed herein together with a PDE4 inhibitor and aβ₂-adrenoreceptor agonist.

In yet another aspect, provided herein is a combination comprising acompound disclosed herein together with an anticholinergic and a PDE-4inhibitor.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical composition and thus pharmaceuticalcompositions comprising a combination as defined above together with apharmaceutically acceptable excipient or carrier represent a furtheraspect of the invention.

The individual compounds of such combinations may be administered eithersequentially or simultaneously in separate or combined pharmaceuticalformulations. In one embodiment, the individual compounds will beadministered simultaneously in a combined pharmaceutical formulation.Appropriate doses of known therapeutic agents will readily beappreciated by those skilled in the art.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a compound disclosed hereintogether with another therapeutically active agent.

In one embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with achemotherapeutic agents.

In one embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with ananti-proliferative agents.

In one embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with a PDE4inhibitor.

In another embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with aβ₂-adrenoreceptor agonist.

In another embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with acorticosteroid.

In another embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with a non-steroidalGR agonist.

In another embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with ananticholinergic agent.

In still another embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with anantihistamine.

In another embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with ananti-inflammatory agents.

In another embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with animmunomodulators.

In another embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with an agents fortreating atherosclerosis

In another embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with an agents fortreating pulmonary fibrosis.

In the field of medical oncology it is normal practice to use acombination of different forms of treatment to treat each patient withcancer. In medical oncology the other component(s) of such conjointtreatment in addition to compositions disclosed herein may be, forexample, surgery, radiotherapy, chemotherapy, signal transductioninhibitors or modulators (e.g. kinase inhibitors or modulators) and/ormonoclonoal antibodies.

A compound disclosed herein may also be used to advantage in combinationwith each other or in combination with other therapeutic agents,especially other antiproliferative agents. Such antiproliferative agentsinclude, but are not limited to, aromatase inhibitors; antiestrogens;topoisomerase I inhibitors; topoisomerase II inhibitors; microtubuleactive agents; alkylating agents; histone deacetylase inhibitors;compounds that induce cell differentiation processes; cyclooxygenaseinhibitors; MMP inhibitors; mTOR inhibitors; antineoplasticantimetabolites; platin compounds; compounds targeting/decreasing aprotein or lipid kinase activity and further anti-angiogenic compounds;compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase; gonadorelin agonists; anti-androgens; methionineaminopeptidase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; agents used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors; temozolomide (TEMODAL®); and leucovorin.

The term “aromatase inhibitor”, as used herein, relates to a compoundwhich inhibits the estrogen production, i.e., the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to, steroids,especially atamestane, exemestane and formestane; and, in particular,nonsteroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane can be administered,e.g., in the form as it is marketed, e.g., under the trademarkAROMASIN®. Formestane can be administered, e.g., in the form as it ismarketed, e.g., under the trademark LENTARON®. Fadrozole can beadministered, e.g., in the form as it is marketed, e.g., under thetrademark AFEMA®. Anastrozole can be administered, e.g., in the form asit is marketed, e.g., under the trademark ARIMIDEX®. Letrozole can beadministered, e.g., in the form as it is marketed, e.g., under thetrademark FEMARA® or FEMAR®. Aminoglutethimide can be administered,e.g., in the form as it is marketed, e.g., under the trademarkORIMETEN®. A combination of the invention comprising a chemotherapeuticagent which is an aromatase inhibitor is particularly useful for thetreatment of hormone receptor positive tumors, e.g., breast tumors.

The term “anti-estrogen”, as used herein, relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to, tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen can be administered, e.g., inthe form as it is marketed, e.g., under the trademark NOLVADEX®.Raloxifene hydrochloride can be administered, e.g., in the form as it ismarketed, e.g., under the trademark EVISTA®. Fulvestrant can beformulated as disclosed in U.S. Pat. No. 4,659,516 or it can beadministered, e.g., in the form as it is marketed, e.g., under thetrademark FASLODEX®. A combination of the invention comprising achemotherapeutic agent which is an antiestrogen is particularly usefulfor the treatment of estrogen receptor positive tumors, e.g., breasttumors.

The term “anti-androgen”, as used herein, relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (CASODEX®), which canbe formulated, e.g., as disclosed in U.S. Pat. No. 4,636,505.

The term “gonadorelin agonist”, as used herein, includes, but is notlimited to, abarelix, goserelin and goserelin acetate. Goserelin isdisclosed in U.S. Pat. No. 4,100,274 and can be administered, e.g., inthe form as it is marketed, e.g., under the trademark ZOLADEX®. Abarelixcan be formulated, e.g., as disclosed in U.S. Pat. No. 5,843,901. Theterm “topoisomerase I inhibitor”, as used herein, includes, but is notlimited to, topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148 (compound A1 in WO 99/17804). Irinotecan can beadministered, e.g., in the form as it is marketed, e.g., under thetrademark CAMPTOSAR®. Topotecan can be administered, e.g., in the formas it is marketed, e.g., under the trademark HYCAMTIN®.

The term “topoisomerase II inhibitor”, as used herein, includes, but isnot limited to, the anthracyclines, such as doxorubicin, includingliposomal formulation, e.g., CAELYX®; daunorubicin; epirubicin;idarubicin; nemorubicin; the anthraquinones mitoxantrone andlosoxantrone; and the podophillotoxines etoposide and teniposide.Etoposide can be administered, e.g., in the form as it is marketed,e.g., under the trademark ETOPOPHOS®. Teniposide can be administered,e.g., in the form as it is marketed, e.g., under the trademark VM26-BRISTOL®. Doxorubicin can be administered, e.g., in the form as it ismarketed, e.g., under the trademark ADRIBLASTIN® or ADRIAMYCIN®.

Epirubicin can be administered, e.g., in the form as it is marketed,e.g., under the trademark FARMORUBICIN®. Idarubicin can be administered,e.g., in the form as it is marketed, e.g., under the trademark ZAVEDOS®.Mitoxantrone can be administered, e.g., in the form as it is marketed,e.g., under the trademark NOVANTRON®.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing agents and microtublin polymerizationinhibitors including, but not limited to, taxanes, e.g., paclitaxel anddocetaxel; vinca alkaloids, e.g., vinblastine, especially vinblastinesulfate; vincristine, especially vincristine sulfate and vinorelbine;discodermolides; cochicine; and epothilones and derivatives thereof,e.g., epothilone B or D or derivatives thereof. Paclitaxel may beadministered, e.g., in the form as it is marketed, e.g., TAXOL®.Docetaxel can be administered, e.g., in the form as it is marketed,e.g., under the trademark TAXOTERE®. Vinblastine sulfate can beadministered, e.g., in the form as it is marketed, e.g., under thetrademark VINBLASTIN R.P®. Vincristine sulfate can be administered,e.g., in the form as it is marketed, e.g., under the trademarkFARMISTIN®. Discodermolide can be obtained, e.g., as disclosed in U.S.Pat. No. 5,010,099. Also included are epothilone derivatives which aredisclosed in WO 98/10121, U.S. Pat. No. 6,194,181, WO 98/25929, WO98/08849, WO 99/43653, WO 98/22461 and WO 00/31247. Especially preferredare epothilone A and/or B.

The term “alkylating agent”, as used herein, includes, but is notlimited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNUor Gliadel). Cyclophosphamide can be administered, e.g., in the form asit is marketed, e.g., under the trademark CYCLOSTIN®. Ifosfamide can beadministered, e.g., in the form as it is marketed, e.g., under thetrademark HOLOXAN®.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes compounds disclosed in WO02/22577, especiallyN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamideand pharmaceutically acceptable salts thereof. It further especiallyincludes suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU; capecitabine; gemcitabine; DNA demethylatingagents, such as 5-azacytidine and decitabine; methotrexate andedatrexate; and folic acid antagonists, such as pemetrexed. Capecitabinecan be administered, e.g., in the form as it is marketed, e.g., underthe trademark XELODA®. Gemcitabine can be administered, e.g., in theform as it is marketed, e.g., under the trademark GEMZAR®. Also includedis the monoclonal antibody trastuzumab which can be administered, e.g.,in the form as it is marketed, e.g., under the trademark HERCEPTIN®.

The term “platin compound”, as used herein, includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g., underthe trademark CARBOPLAT®. Oxaliplatin can be administered, e.g., in theform as it is marketed, e.g., under the trademark ELOXATIN®.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds”, as used herein, includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, e.g.,

a) compounds targeting, decreasing or inhibiting the activity of theplatelet-derived growth factor-receptors (PDGFR), such as compoundswhich target, decrease or inhibit the activity of PDGFR, especiallycompounds which inhibit the PDGF receptor, e.g., aN-phenyl-2-pyrimidine-amine derivative, e.g., imatinib, SU101, SU6668and GFB-111;b) compounds targeting, decreasing or inhibiting the activity of thefibroblast growth factor-receptors (FGFR);c) compounds targeting, decreasing or inhibiting the activity of theinsulin-like growth factor receptor I (IGF-IR), such as compounds whichtarget, decrease or inhibit the activity of IGF-IR, especially compoundswhich inhibit the IGF-IR receptor, such as those compounds disclosed inWO 02/092599;d) compounds targeting, decreasing or inhibiting the activity of the Trkreceptor tyrosine kinase family;e) compounds targeting, decreasing or inhibiting the activity of the Axlreceptor tyrosine kinase family;f) compounds targeting, decreasing or inhibiting the activity of thec-Met receptor;g) compounds targeting, decreasing or inhibiting the activity of theKit/SCFR receptor tyrosine kinase;h) compounds targeting, decreasing or inhibiting the activity of thec-kit receptor tyrosine kinases—(part of the PDGFR family), such ascompounds which target, decrease or inhibit the activity of the c-Kitreceptor tyrosine kinase family, especially compounds which inhibit thec-Kit receptor, e.g., imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family and their gene-fusion products, e.g., BCR-Ablkinase, such as compounds which target decrease or inhibit the activityof c-Abl family members and their gene fusion products, e.g., aN-phenyl-2-pyrimidine-amine derivative, e.g., imatinib, PD180970, AG957,NSC 680410 or PD173955 from ParkeDavis;j) compounds targeting, decreasing or inhibiting the activity of membersof the protein kinase C (PKC) and Raf family of serine/threoninekinases, members of the MEK, SRC, JAK, FAK, PDK and Ras/MAPK familymembers, or PI(3) kinase family, or of the PI(3)-kinase-related kinasefamily, and/or members of the cyclin-dependent kinase family (CDK) andare especially those staurosporine derivatives disclosed in U.S. Pat.No. 5,093,330, e.g., midostaurin; examples of further compounds include,e.g., UCN-01; safingol; BAY 43-9006; Bryostatin 1; Perifosine;llmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;LY333531/LY379196; isochinoline compounds, such as those disclosed in WO00/09495; FTIs; PD184352; or QAN697 (a PI3K inhibitor);k) compounds targeting, decreasing or inhibiting the activity ofprotein-tyrosine kinase inhibitors, such as compounds which target,decrease or inhibit the activity of protein-tyrosine kinase inhibitorsinclude imatinib mesylate (GLEEVEC®) or tyrphostin. A tyrphostin ispreferably a low molecular weight (Mr<1500) compound, or apharmaceutically acceptable salt thereof, especially a compound selectedfrom the benzylidenemalonitrile class or the S-arylbenzenemalonirile orbisubstrate quinoline class of compounds, more especially any compoundselected from the group consisting of Tyrphostin A23/RG-50810, AG 99,Tyrphostin AG 213, Tyrphostin AG 1748, Tyrphostin AG 490, TyrphostinB44, Tyrphostin B44 (+) enantiomer, Tyrphostin AG 555, AG 494,Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester,NSC 680410, adaphostin; andl) compounds targeting, decreasing or inhibiting the activity of theepidermal growth factor family of receptor tyrosine kinases (EGFR,ErbB2, ErbB3, ErbB4 as homo- or hetero-dimers), such as compounds whichtarget, decrease or inhibit the activity of the epidermal growth factorreceptor family are especially compounds, proteins or antibodies whichinhibit members of the EGF receptor tyrosine kinase family, e.g., EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,and are in particular those compounds, proteins or monoclonal antibodiesgenerically and specifically disclosed in WO 97/02266, e.g., thecompound of Example 39, or in EP 0564409; WO 99/03854; EP 0520722; EP0566226; EP 0787722; EP 0837063; U.S. Pat. No. 5,747,498; WO 98/10767;WO 97/30034; WO 97/49688; WO 97/38983 and, especially, WO 96/30347,e.g., compound known as CP 358774; WO 96/33980, e.g., compound ZD 1839;and WO 95/03283, e.g., compound ZM105180, e.g., trastuzumab (HERCEPTIN),cetuximab, Iressa, Tarceva, OSI-774, CI-1033, EKB-569, GW-2016, E1.1,E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3; and7H-pyrrolo-[2,3-d]pyrimidine derivatives which are disclosed in WO03/013541.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g., unrelated to protein or lipid kinaseinhibition, e.g., thalidomide (THALOMID®) and TNP-470.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are, e.g., inhibitors of phosphatase 1, phosphatase2A, PTEN or CDC25, e.g., okadaic acid or a derivative thereof.

Compounds that induce cell differentiation processes are e.g. retinoicacid, α-, γ- or δ-tocopherol or α-, γ- or δ-tocotrienol.

The term cyclooxygenase inhibitor, as used herein, includes, but is notlimited to, e.g., Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(CELEBREX®), rofecoxib (VIOXX®), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, e.g.,5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid orlumiracoxib.

The term “bisphosphonates”, as used herein, includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. “Etridonic acid” can beadministered, e.g., in the form as it is marketed, e.g., under thetrademark DIDRONEL®. “Clodronic acid” can be administered, e.g., in theform as it is marketed, e.g., under the trademark BONEFOS®. “Tiludronicacid” can be administered, e.g., in the form as it is marketed, e.g.,under the trademark SKELID®. “Pamidronic acid” can be administered,e.g., in the form as it is marketed, e.g., under the trademark AREDIA™.“Alendronic acid” can be administered, e.g., in the form as it ismarketed, e.g., under the trademark FOSAMAX®. “Ibandronic acid” can beadministered, e.g., in the form as it is marketed, e.g., under thetrademark BONDRANAT®. “Risedronic acid” can be administered, e.g., inthe form as it is marketed, e.g., under the trademark ACTONEL®.“Zoledronic acid” can be administered, e.g., in the form as it ismarketed, e.g., under the trademark ZOMETA®.

The term “mTOR inhibitors” relates to compounds which inhibit themammalian target of rapamycin (mTOR) and which possess antiproliferativeactivity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779and ABT578.

The term “heparanase inhibitor”, as used herein, refers to compoundswhich target, decrease or inhibit heparin sulphate degradation. The termincludes, but is not limited to, PI-88.

The term “biological response modifier”, as used herein, refers to alymphokine or interferons, e.g., interferon γ.

The term “inhibitor of Ras oncogenic isoforms”, e.g., H-Ras, K-Ras orN-Ras, as used herein, refers to compounds which target, decrease orinhibit the oncogenic activity of Ras, e.g., a “farnesyl transferaseinhibitor”, e.g., L-744832, DK8G557 or R1 15777 (Zarnestra).

The term “telomerase inhibitor”, as used herein, refers to compoundswhich target, decrease or inhibit the activity of telomerase. Compoundswhich target, decrease or inhibit the activity of telomerase areespecially compounds which inhibit the telomerase receptor, e.g.,telomestatin.

The term “methionine aminopeptidase inhibitor”, as used herein, refersto compounds which target, decrease or inhibit the activity ofmethionine aminopeptidase. Compounds which target, decrease or inhibitthe activity of methionine aminopeptidase are, e.g., bengamide or aderivative thereof.

The term “proteasome inhibitor”, as used herein, refers to compoundswhich target, decrease or inhibit the activity of the proteasome.Compounds which target, decrease or inhibit the activity of theproteasome include, e.g., PS-341 and MLN 341.

The term “matrix metalloproteinase inhibitor” or “MMP inhibitor”, asused herein, includes, but is not limited to, collagen peptidomimeticand nonpeptidomimetic inhibitors, tetracycline derivatives, e.g.,hydroxamate peptidomimetic inhibitor batimastat and its orallybioavailable analogue marimastat (BB-2516), prinomastat (AG3340),metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B orAAJ996.

The term “agents used in the treatment of hematologic malignancies”, asused herein, includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, e.g., compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors,e.g., compounds which target, decrease or inhibit anaplastic lymphomakinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,e.g., PKC412, midostaurin, a staurosporine derivative, SU1 1248 andMLN518.

The term “HSP90 inhibitors”, as used herein, includes, but is notlimited to, compounds targeting, decreasing or inhibiting the intrinsicATPase activity of HSP90; degrading, targeting, decreasing or inhibitingthe HSP90 client proteins via the ubiquitin proteasome pathway.Compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90 are especially compounds, proteins or antibodies whichinhibit the ATPase activity of HSP90, e.g., 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative, othergeldanamycin related compounds, radicicol and HDAC inhibitors.

The term “antiproliferative antibodies”, as used herein, includes, butis not limited to, trastuzumab (HERCEPTIN™), Trastuzumab-DM1, erlotinib(TARCEVA™), bevacizumab (AVASTIN™), rituximab (RITUXAN®), PR064553(anti-CD40) and 2C4 antibody. By antibodies is meant, e.g., intactmonoclonal antibodies, polyclonal antibodies, multispecific antibodiesformed from at least two intact antibodies, and antibodies fragments solong as they exhibit the desired biological activity. For the treatmentof acute myeloid leukemia (AML), compounds disclosed herein can be usedin combination with standard leukemia therapies, especially incombination with therapies used for the treatment of AML. In particular,compounds disclosed herein can be administered in combination with,e.g., farnesyl transferase inhibitors and/or other drugs useful for thetreatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16,Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.

A compound disclosed herein may also be used to advantage in combinationwith each other or in combination with other therapeutic agents,especially other anti-malarial agents. Such anti-malarial agentsinclude, but are not limited to proguanil, chlorproguanil, trimethoprim,chloroquine, mefloquine, lumefantrine, atovaquone,pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine,quinidine, amodiaquine, amopyroquine, sulphonamides, artemisinin,arteflene, artemether, artesunate, primaquine, inhaled NO, L-arginine,Dipropylenetri-amine NONOate (NO donor), Rosiglitzone (PPAR-γ agonist),activated charcoal, Erythropoietin, Levamisole, and pyronaridine.

A compound disclosed herein may also be used to advantage in combinationwith each other or in combination with other therapeutic agents, such asused for the treatment of Leishmaniosis, Trypanosomiasis, Toxoplasmosisand Neurocysticercosis. Such agents include, but are not limited tochloroquine sulfate, atovaquone-proguanil, artemether-lumefantrine,quinine-sulfate, artesunate, quinine, doxycycline, clindamycin,meglumine antimoniate, sodium stibogluconate, miltefosine, ketoconazole,pentamidine, amphotericin B (AmB), liposomal-AmB, paromomycine,eflornithine, nifurtimox, suramin, melarsoprol, prednisolone,benznidazole, sulfadiazine, pyrimethamine, clindamycin, trimetropim,sulfamethoxazole, azitromycin, atovaquone, dexamethasone, praziquantel,albendazole, beta-lactams, fluoroquinolones, macrolides,aminoglycosides, sulfadiazine and pyrimethamine.

The structure of the active agents identified by code nos., generic ortrade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g., PatentsInternational, e.g., IMS World Publications.

The above-mentioned compounds, which can be used in combination with acompound disclosed herein, can be prepared and administered as describedin the art, such as in the documents cited above.

A compound disclosed herein may also be used to advantage in combinationwith known therapeutic processes, e.g., the administration of hormonesor especially radiation. A compound disclosed herein may in particularbe used as a radiosensitizer, especially for the treatment of tumorswhich exhibit poor sensitivity to radiotherapy.

By “combination”, there is meant either a fixed combination in onedosage unit form, or a kit of parts for the combined administrationwhere a compound disclosed herein and a combination partner may beadministered independently at the same time or separately within timeintervals that especially allow that the combination partners show acooperative, e.g., synergistic, effect or any combination thereof. Theterms “coadministration” or “combined administration” or the like asutilized herein are meant to encompass administration of the selectedcombination partner to a single subject in need thereof (e.g. apatient), and are intended to include treatment regimens in which theagents are not necessarily administered by the same route ofadministration or at the same time. The term “pharmaceuticalcombination” as used herein means a product that results from the mixingor combining of more than one active ingredient and includes both fixedand non-fixed combinations of the active ingredients. The term “fixedcombination” means that the active ingredients, e.g. a compounddisclosed herein and a combination partner, are both administered to apatient simultaneously in the form of a single entity or dosage. Theterm “non-fixed combination” means that the active ingredients, e.g. acompound disclosed herein and a combination partner, are bothadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific time limits, wherein suchadministration provides therapeutically effective levels of the twocompounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of three or more activeingredients.

Methods of Treatment

In one embodiment, the methods of treatment disclosed herein compriseadministering a safe and effective amount of a compound or apharmaceutically composition disclosed herein to a patient in needthereof. Individual embodiments disclosed herein include methods oftreating any one of the above-mentioned disorders by administering asafe and effective amount of a compound disclosed herein or apharmaceutical composition containing a compound disclosed herein to apatient in need thereof.

In one embodiment, the compounds disclosed herein or pharmaceuticallycompositions containing the compounds disclosed herein may beadministered by any suitable route of administration, including bothsystemic administration and topical administration. Systemicadministration includes oral administration, parenteral administration,transdermal administration and rectal administration. Parenteraladministration is typically by injection or infusion, includingintravenous, intramuscular, and subcutaneous injection or infusion.Topical administration includes application to the skin as well asintraocular, otic, intravaginal, inhaled and intranasal administration.In one embodiment, the compounds disclosed herein or pharmaceuticalcompositions containing the compounds disclosed herein may beadministered orally. In another embodiment, the compounds disclosedherein or pharmaceutically compositions containing the compoundsdisclosed herein may be administered by inhalation. In a furtherembodiment, the compounds disclosed herein or pharmaceuticalcompositions containing the compounds disclosed herein may beadministered intranasally.

In another embodiment, the compounds disclosed herein orpharmaceutically compositions containing the compounds disclosed hereinmay be administered once or according to a dosing regimen wherein anumber of doses are administered at varying intervals of time for agiven period of time. For example, doses may be administered one, two,three, or four times per day. In one embodiment, a dose is administeredonce per day. In a further embodiment, a dose is administered twice perday. Doses may be administered until the desired therapeutic effect isachieved or indefinitely to maintain the desired therapeutic effect.Suitable dosing regimens for a compound disclosed herein or apharmaceutical composition containing a compound disclosed herein dependon the pharmacokinetic properties of that compound, such as absorption,distribution, and half-life, which can be determined by the skilledartisan. In addition, suitable dosing regimens, including the durationsuch regimens are administered, for a compound disclosed herein or apharmaceutical composition containing a compound disclosed herein dependon the disorder being treated, the severity of the disorder beingtreated, the age and physical condition of the patient being treated,the medical history of the patient to be treated, the nature ofconcurrent therapy, the desired therapeutic effect, and like factorswithin the knowledge and expertise of the skilled artisan. It will befurther understood by such skilled artisans that suitable dosingregimens may require adjustment given an individual patient's responseto the dosing regimen or over time as individual patient needs change.

The compound of the present invention may be administered eithersimultaneously with, or before or after, one or more other therapeuticagent. The compound of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the other agents.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease. The above-cited dosageproperties are demonstrable in vitro and in vivo tests usingadvantageously mammals, e.g., mice, rats, dogs, monkeys or isolatedorgans, tissues and preparations thereof. The compounds of the presentinvention can be applied in vitro in the form of solutions, e.g.,aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution.

In one embodiment, the therapeutically effective dose is from about 0.1mg to about 2,000 mg per day of a compound provided herein. Thepharmaceutical compositions therefore should provide a dosage of fromabout 0.1 mg to about 2000 mg of the compound. In certain embodiments,pharmaceutical dosage unit forms are prepared to provide from about 1 mgto about 2000 mg, from about 10 mg to about 1000 mg, from about 20 mg toabout 500 mg or from about 25 mg to about 250 mg of the essential activeingredient or a combination of essential ingredients per dosage unitform. In certain embodiments, the pharmaceutical dosage unit forms areprepared to provide about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg,500 mg, 1000 mg or 2000 mg of the essential active ingredient.

Additionally, the compounds disclosed herein may be administered asprodrugs. As used herein, a “prodrug” of a compound disclosed herein isa functional derivative of the compound which, upon administration to apatient, eventually liberates the compound disclosed herein in vivo.Administration of a compound disclosed herein as a prodrug may enablethe skilled artisan to do one or more of the following: (a) modify theonset of the activity of the compound in vivo; (b) modify the durationof action of the compound in vivo; (c) modify the transportation ordistribution of the compound in vivo; (d) modify the solubility of thecompound in vivo; and (e) overcome a side effect or other difficultyencountered with the compound. Typical functional derivatives used toprepare prodrugs include modifications of the compound that arechemically or enzymatically cleavable in vivo. Such modifications, whichinclude the preparation of phosphates, amides, esters, thioesters,carbonates, and carbamates, are well known to those skilled in the art.

General Synthetic Procedures

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention.

Generally, the compounds in this invention may be prepared by methodsdescribed herein, wherein the substituents are as defined for Formula(I) and Formula (II), above, except where further noted. The followingnon-limiting schemes and examples are presented to further exemplify theinvention. Persons skilled in the art will recognize that the chemicalreactions described herein may be readily adapted to prepare a number ofother compounds of the invention, and alternative methods for preparingthe compounds of this invention are deemed to be within the scope ofthis invention. For example, the synthesis of non-exemplified compoundsaccording to the invention may be successfully performed bymodifications apparent to those skilled in the art, e.g., byappropriately protecting interfering groups, by utilizing other suitablereagents known in the art other than those described, and/or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving applicability for preparing other compounds of the invention.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company, ArcoChemical Company and Alfa Chemical Company, Shanghai Medpep. Co Ltd,Aladdin-Shanghai Jinchun Reagents, Ltd, and were used without furtherpurification unless otherwise indicated. Common solvents were purchasedfrom commercial suppliers such as Shantou XiLong Chemical Factory,Guangdong Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou ReagentChemical Factory, Tainjin YuYu Fine Chemical Ltd., Qingdao TenglongReagent Chemical Ltd., and Qingdao Ocean Chemical Factory.

Anhydrous THF, dioxane, toluene, and ether were obtained by refluxingthe solvent with sodium. Anhydrous CH₂Cl₂ and CHCl₃ were obtained byrefluxing the solvent with CaH₂. EtOAc, PE, hexanes, DMA and DMF weretreated with anhydrous Na₂SO₄ prior use.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was conducted using a silica gel column. Silicagel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory.

¹H NMR spectra were recorded with a Bruker 400 MHz or 600 MHzspectrometer at ambient temperature. ¹H NMR spectra were obtained asCDCl₃, DMSO-d₆, CD₃OD or acetone-d₆ solutions (reported in ppm), usingTMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. Whenpeak multiplicities are reported, the following abbreviations are used:s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd(doublet of doublets), dt (doublet of triplets), td (triplet ofdoublets). Coupling constants J, when given, are reported in Hertz (Hz).

Low-resolution mass spectral (MS) data were generally determined on anAgilent 6120 quadrupole HPLC-MS (Zorbax SB-C18, 2.1×30 mm, 3.5 micron, 6minutes run, 0.6 mL/min flow rate, 5% to 95% (0.1% formic acid in CH₃CN)in (0.1% formic acid in H₂O)) with UV detection at 210/254 nm andelectrospray ionization (ESI).

Purities of compounds were assessed by Agilent 1260 pre-HPLC or Caleseppump 250 pre-HPLC (column: NOVASEP 50/80 mm DAC) with UV detection at210 nm and 254 nm.

The following abbreviations are used throughout the specification:

AcOH, HAc, CH₃COOH acetic acid

Ac₂O acetic anhydride

BnBr benzyl bromide

BOC, Boc butyloxycarbony

(Boc)₂O di-tert-butyl dicarbonate

BH₃.DMS borane-methyl sulfide complex

BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

n-BuOH n-butyl alcohol

Cs₂CO₃ cesium carbonate

CH₂Cl₂, DCM methylene chloride

CDCl₃ chloroform deuterated

CH₃I iodomethane

DIEA, DIPEA, i-Pr₂NEt N,N-diisopropylethylamine

DMF dimethylformamide

DMP dimethyl phthalate

DMAP 4-dimethylaminopyridine, N,N-dimethylpyridin-4-amine

DMSO dimethylsulfoxide

DHP dihydropyran

DIAD diisopropyl azodicarboxylate

PPTs pyridinium toluene-4-sulphonate

Et₃N, TEA triethylamine

EtOAc, EA ethyl acetate

EtOH ethanol

Et₂O diethyl ether

EDCI N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride

g gram

h hour

HATU 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

HCl hydrochloric acid

HOAT 1-hydroxy-7-azabenzotriazole

KOH potassium hydroxide

KMnO₄ potassium permanganate

K₂CO₃ potassium carbonate

LiCl lithium chloride

LiHMDS, LHMDS lithium bis(trimethylsilyl)amide

LAH lithium aluminium hydride

MeCN, CH₃CN acetonitrile

MsCl methanesulfonyl chloride

(NH₄)₂SO₄ ammonium sulfate

NH₄Cl ammonium chloride

NaH sodium hydride

NaBH₃CN sodium cyanoborohydride

Na₂CO₃ sodium carbonate

NaHCO₃ sodium bicarbonate

NaOH sodium hydroxide

Na₂SO₄ sodium sulfate

Na₂S₂O₃ sodium thiosulfate

NaOAc ammonium acetate

NBS bromosuccinimide

MeOH methanol

mCPBA 3-chlorobenzenecarboperoxoic acid

mL, ml milliliter

Pd/C palladium on carbon

PTSA p-toluenesulfonic acid

PE petroleum ether (60-90° C.)

PDC pyridinium dichromate

RT, rt, r.t. room temperature

PTSA p-toluenesulfonamide

Pd(OAc)₂ palladium diacetate

Pd/C palladium on activated carbon

PCl₅ phosphorus pentachloride

PDC pyridinium dichromate

Rt retention time

THF tetrahydrofuran

TBAF tetrabutylammonium fluoride

TFAA trifluoroacetic anhydride

TFA, CF₃COOH trifluoroacetic acid

Ti(Oi-Pr)₄ titanium tetraisopropanolate

TsCl tosyl chloride

Representative synthetic procedures for the preparation of the compoundsdisclosed herein is outlined below in following Scheme 1 to Scheme 5.Unless otherwise indicated, each of Z, Z¹, W, W₁, A, R¹, R², R³, R^(3a),R⁴, R^(4a), R⁵, R^(5a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R¹², R¹³,R¹⁴ n and m carry the definitions set forth above in connection withFormula (I) and Formula (II); p is 0, 1, 2, 3, or 4; q is 0, 1, 2 or 3;PG is a protecting group; each R^(ss) is independently R³, R^(3a), R⁴,R^(4a), R⁵, R^(5a), R⁶, R^(6a), R⁷, R^(7a), R⁸ or R^(8a).

Some compounds having Formula (6) or Formula (7) can be prepared by ageneral method illustrated in Scheme 1 and described in details in theExamples. As showing in Scheme 1, substituted dichloropyrimidinecompound (1) is reacted with optionally substituted heterocycliccompound (2) with an aid of a base, such as Et₃N, DIPEA or Cs₂CO₃ togive optionally substituted heteroaryl compound (3). Compound (3) isthen coupled with optionally substituted aminopyrazole (4) or ahydrochloride thereof in the presence of a base, such as DIPEA, Et₃N, orin the presence of an acid, such as trifluoroacetic acid, a solution ofHCl in EtOAc, or in the presence of a suitable Pd catalyst, such asPd(OAc)₂, to afford the compound (5). The protecting group of compound(5) is removed under acidic conditions, such as trifluoroacetic acid, asolution of HCl in EtOAc, or with an aid of hydrazine hydrate, or anyother appropriate condition, such as with the aid of TBAF to give thedesired protein kinase inhibitor (6). Other protein kinase inhibitorhaving Formula (7) is obtained by introducing various substituents tothe compound (6) under appropriate conditions.

Some compounds having Formula (10) or Formula (11) can be prepared by ageneral method illustrated in Scheme 2 and described in details in theExamples. As showing in Scheme 2, Compound (3) is coupled withoptionally substituted aminopyrazole (8) or a hydrochloride thereof inthe presence of a base, such as DIPEA, Et₃N, Cs₂CO₃ or in the presenceof an acid, such as trifluoroacetic acid, a solution of HCl in EtOAc, orin the presence of a suitable Pd catalyst, such as Pd(OAc)₂, to affordthe compound (9). The protecting group of compound (9) is removed underacidic conditions, such as trifluoroacetic acid, a solution of HCl inEtOAc, or with an aid of hydrazine hydrate, or any other appropriatecondition, such as with the aid of TBAF to give the desired proteinkinase inhibitor (10). Other desired protein kinase inhibitor havingFormula (11) is obtained by introducing various substituents to thecompound (10) under appropriate conditions.

Some compounds having Formula (14) or Formula (15) can be prepared by ageneral method illustrated in Scheme 3 and described in details in theExamples. As showing in Scheme 3, Compound (3) is coupled withoptionally substituted aminoimidazole (12) or a hydrochloride thereof inthe presence of a suitable Pd catalyst, such as Pd(OAc)₂, affords thecompound (13). The protecting group of compound (13) is removed underacidic conditions, such as trifluoroacetic acid, a solution of HCl inEtOAc, or with an aid of hydrazine hydrate, or any other appropriatecondition, such as with the aid of TBAF to give the desired proteinkinase inhibitor (14). Other desired protein kinase inhibitor havingFormula (15) is obtained by introducing various substituents to thecompound (14) under appropriate conditions.

Some compounds having Formula (19) can be prepared by a general methodillustrated in Scheme 4 and described in details in the Examples. Asshowing in Scheme 4, the protecting group of compound (3) is removedunder acidic conditions, such as trifluoroacetic acid, a solution of HClin EtOAc, or with an aid of hydrazine hydrate, or any other appropriatecondition, such as with the aid of TBAF to give the compound (16). Then,various substituents are introduced to the compound (16) underappropriate conditions to give the compound (17). Compound (17) iscoupled with optionally substituted aminoazole compound (18) or ahydrochloride thereof in the presence of a base, such as DIPEA, Et₃N,Cs₂CO₃ or in the presence of a suitable Pd catalyst, such as Pd(OAc)₂,to afford the desired protein kinase inhibitor (19).

Some compounds having Formula (25) or Formula (26) can be prepared by ageneral method illustrated in Scheme 5 and described in details in theExamples. As showing in Scheme 5, optionally substituteddichloropyrimidine compound (20) is reacted with optionally substitutedheterocyclic compound (21) with an aid of a base, such as Et₃N, DIPEA togive optionally substituted heteroaryl compound (22). Compound (22) isthen coupled with optionally substituted 1-methyl-H-pyrazole-4-amine(23) or a hydrochloride thereof in the presence of a base, such asDIPEA, Et₃N, Cs₂CO₃ or in the presence of an acid, such astrifluoroacetic acid, a solution of HCl in EtOAc, or in the presence ofa suitable Pd catalyst, such as Pd(OAc)₂, to afford the compound (24).The protecting group of compound (24) is removed under acidicconditions, such as trifluoroacetic acid, a solution of HCl in EtOAc, orwith an aid of hydrazine hydrate, or any other appropriate condition,such as with the aid of TBAF to give the other protein kinase inhibitorhaving Formula (26) is obtained by introducing various substituents tothe compound (25) under appropriate conditions.

EXAMPLES Example 11-(5-((5-chloro-2-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone

Step 1) tert-butyl 3a,4,7,7a-tetrahydro-1H-isoindole-2(3H)-carboxylate

To a suspension of LAH (22.80 g, 600 mmol) in THF (600 mL) at 0° C. wasadded tetrahydrophthalimide (39.45 g, 260.9 mmol) portion-wise. Afteraddition, the reaction mixture was stirred at 60° C. for 18 h, thencooled down to 0° C. and quenched carefully with water (25 mL), followedby 15% KOH aqueous solution (25 mL) and another 75 mL of water. Theresulting mixture was stirred at rt for 1 h and filtered through a padof Celite. Then the filtrate was washed with DCM (500 mL) andconcentrated in vacuo to give isoindole as yellow oil, which was used inthe next step without purification.

Accordingly, the isoindole in DCM (300 mL) was treated with Et₃N (39.61g, 391.4 mmol) and (Boc)₂O (68.32 g, 313.1 mmol) at 0° C. for 0.5 h, andthen warmed to rt and stirred for another 21 h. The mixture wasconcentrated in vacuo and the residue was dissolved in EtOAc (600 mL),then the resulting solution was washed with citric acid aqueous solution(1 M, 130 mL×2), followed by saturated NaHCO₃ (2×130 mL) and brine (250mL). The separated organic layer was dried over anhydrous Na₂SO₄, thenfiltered and concentrated in vacuo. The residue was purified by silicagel column chromatography (EtOAc/PE (v/v)=1/5) to give the titlecompound as orange red oil (45.00 g, yield 77.3%).

LC-MS (ESI, pos. ion) m/z: 168.2 [(M−C₄H₈)+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 5.64 (s, 2H), 3.40 (m, 2H), 3.16 (m,1H), 3.07 (m, 1H), 2.25 (m, 4H), 1.90 (m, 2H), 1.46 (s, 9H).

Step 2) 2,2′-(1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid

To a solution of tert-butyl3a,4,7,7a-tetrahydro-1H-isoindole-2(3H)-carboxylate (4.91 g, 22 mmol)and (NH₄)₂SO₄ (1.55 g, 12 mmol) in H₂O (40 mL) was added KMnO₄ (8.20 g,52 mmol) portionwise at 5° C. in 0.5 h. The reaction mixture was stirredat 5° C. for 6 h, then filtered and the filter cake was washed with H₂O(40 mL×3). The filtrate was extracted with CH₂Cl₂ (40 mL×3) and theaqueous layer was adjusted to pH=2-3 with 3 M HCl aqueous solution, thenextracted with EtOAc (50 mL×3). The combined organic phases were washedwith brine (50 mL×3), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound as a pale yellow solid(4.52 g, yield 71.5%).

LC-MS (ESI, pos. ion) m/z: 232.2 [(M−C₄H₈)+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 3.53 (m, 2H), 3.04 (m, 2H), 2.80 (m,2H), 2.44 (m, 4H), 1.43 (s, 9H).

Step 3) tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a suspension of2,2′-(1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid (3.40 g,11.8 mmol) in Ac₂O (21 mL) was added NaOAc (0.78 g, 9.5 mmol) and thereaction mixture was stirred at 120° C. for 3 h. After that, theresulting mixture was cooled down to rt, then filtered and the filtercake was washed with EtOAc (20 mL×2). The filtrate was concentrated invacuo and the residue was purified by silica gel column chromatography(EtOAc/PE (v/v)=1/4) to give the title compound as orange yellow oil(1.38 g, yield 55.0%).

LC-MS (ESI, pos. ion) m/z: 170.2 [(M−C₄H₈)+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 3.69 (m, 2H), 3.00 (m, 4H), 2.61 (dd,J=8.2, 18.4 Hz, 2H), 2.29 (dd, J=5.8, 18.4 Hz, 2H), 1.43 (s, 9H).

Step 4) tert-butyl5-(benzylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a solution of tert-butyl5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (9.57 g, 42.5 mmol)in DCM (170 mL) were added BnNH₂ (4.56 g, 42.5 mmol) and AcOH (2.55 g,42.5 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for0.5 h. Then NaBH(OAc)₃ (18.00 g, 85.0 mmol) was added to the abovemixture. The resulting mixture was stirred at rt for another 20 h, thenquenched with saturated NaHCO₃ aqueous solution (142 mL), and extractedwith DCM (250 mL×3). The combined organic phases were washed with brine(250 mL×3), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by silica gel column chromatography(EtOAc, 100%) to give the title compound as a yellow solid (7.44 g,yield 55.3%).

LC-MS (ESI, pos. ion) m/z: 317.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.31 (m, 4H), 7.26 (m, 1H), 3.79 (s,2H), 3.46 (m, 2H), 3.28 (d, J=8.8 Hz, 1H), 3.16 (tt, J=9.6, 6.9 Hz, 1H),2.55 (m, 2H), 2.28 (s, 2H), 2.22 (m, 2H), 1.45 (s, 9H), 1.31 (m, 2H).

Step 5) tert-butyl5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a solution of tert-butyl5-(benzylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (6.50 g,20.5 mmol) and AcOH (1.23 g, 20.5 mmol) in MeOH (150 mL) was addedPd(OH)₂/C (mass %=10%, 1.00 g), and the suspension was stirred at 40° C.under H₂ atmosphere overnight. The mixture was filtered through a pad ofCelite and the filtrate was concentrated in vacuo. The residue wasdissolved in saturated NaHCO₃ aqueous solution (70 mL) and the mixturewas extracted with DCM (100 mL×3). The combined organic phases werewashed with brine (100 mL×3), dried over anhydrous Na₂SO₄, then filteredand concentrated in vacuo to give the title compound as a yellow solid(4.00 g, yield 86.2%).

LC-MS (ESI, pos. ion) m/z: 227.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 3.44 (m, 2H), 3.31 (m, 3H), 2.98 (br.s, 2H), 2.57 (m, 2H), 2.22 (dt, J=14.0, 7.2 Hz, 2H), 1.44 (s, 9H).

Step 6) tert-butyl5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a solution of 2,4,5-trichloropyrimidine (1.46 g, 7.96 mmol) andtert-butyl 5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3.11g, 13.74 mmol) in EtOH (60 mL) was added Et₃N (2.21 g, 21.84 mmol), andthe reaction mixture was stirred at rt overnight and then concentratedin vacuo. The residue was dissolved in a mixture of EtOAc (50 mL) andwater (50 mL), and the solution was extracted with EtOAc (150 mL×3). Thecombined organic phases were washed with brine (150 mL), dried overanhydrous Na₂SO₄, and then concentrated in vacuo. The residue waspurified by silica gel column chromatography (EtOAc/PE (v/v)=1/5) togive the title compound as a pale yellow solid (2.97 g, yield 100%).

LC-MS (ESI, pos. ion) m/z: 373.0 [M+H]⁺.

Step 7)N-(2,5-dichloropyrimidin-4-yl)octahydrocyclopenta[c]pyrrol-5-amine

To a solution of tert-butyl5-((2,5-dichloropyrimidin-4-yl)amino)-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(3.36 g, 9.00 mmol) in dichloromethane (40 mL) was added a solution ofHCl in EtOAc (20 mL, 80 mmol, 4M). The reaction mixture was stirred atrt for 2 h and concentrated in vacuo. The residue was dissolved in water(20 mL) and the resulting mixture was adjusted to pH=8-9 with asaturated NaHCO₃ aqueous solution, then extracted with DCM/MeOH(v/v=10/1, 50 mL×6). The combined organic phases were washed with brine(100 mL), dried over anhydrous Na₂SO₄, then filtered and concentrated invacuo. The residue was purified by silica gel column chromatography(MeOH/DCM (v/v)=1/10 to 1/5) to give the title compound as a lightyellow solid (2.45 g, yield 99.6%).

LC-MS (ESI, pos. ion) m/z: 273.2 [M+H]⁺.

Step 8)1-(5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone

To a solution ofN-(2,5-dichloropyrimidin-4-yl)octahydrocyclopenta[c]pyrrol-5-amine (1.3g, 4.8 mmol) and acetyl acetate (0.58 g, 5.7 mmol) in dichloromethane(30 mL) was added N,N-diethylethanamine (0.96 g, 9.5 mmol). The mixturewas stirred at room temperature for 10 min. Then the mixture wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=100/1) to give the title product as awhite solid (1.14 g, yield 76%).

LC-MS (ESI, pos. ion) m/z: 315.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.01 (s, 1H), 5.57 (d, J=6.9 Hz, 1H),4.56-4.40 (m, 1H), 3.65-3.55 (m, 3H), 3.39 (dd, J=10.9, 3.4 Hz, 1H),2.84-2.65 (m, 2H), 2.52 (dq, J=15.5, 7.6 Hz, 2H), 2.06 (s, 3H),1.44-1.31 (m, 2H).

Step 9) 2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol

To a solution of 4-nitro-1H-pyrazole (1.01 g, 8.93 mmol) and 2,2-dimethyloxirane (1.94 g, 26.9 mmol) in DMF (20 mL) was added cesiumcarbonate (5.76 g, 17.7 mmol) and the reaction mixture was stirred at100° C. for 3.5 h. The reaction was quenched with water (100 mL) andextracted with EtOAc (250 mL×3). The combined organic phases were washedwith brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (EtOAc/PE (v/v)=1/4) to give the title compound as yellowoil (1.52 g, yield 91.9%).

LC-MS (ESI, pos. ion) m/z: 186.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.26 (s, 1H), 8.07 (s, 1H), 4.11 (s,2H), 1.22 (s, 6H).

Step 10) 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol

To a solution of 2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol (1.52g, 8.21 mmol) in methanol (50 mL) was added Pd/C (150 mg, mass %=10%).The reaction mixture was stirred at rt in a high pressure autoclaveunder 2 MPa H₂ atmosphere overnight and then filtered. The filtrate wasconcentrated in vacuo to give the title compound as purple oil (1.2 g,yield 94%).

LC-MS (ESI, pos. ion) m/z: 156.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.19 (s, 1H), 7.03 (s, 1H), 3.91 (s,2H), 1.82 (s, 2H), 1.13 (s, 6H).

Step 11)1-(5-((5-chloro-2-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone

To a solution of 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol (63 mg,0.405 mmol) and1-(5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone(100 mg, 0.317 mmol) in 1,4-dioxane (6 mL) were added cesium carbonate(207 mg, 0.635 mmol), Pd(OAc)₂ (14 mg, 0.063 mmol) and BINAP (39 mg,0.063 mmol). The reaction mixture was stirred at 100° C. overnight andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/25) to give the title compound as ayellow solid (82 mg, yield 59.6%).

LC-MS (ESI, pos. ion) m/z: 434.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.86 (s, 1H), 7.74 (s, 1H), 7.60 (s,1H), 6.77 (s, 1H), 5.24 (d, J=7.2 Hz, 1H), 4.40 (m, 1H), 4.01 (s, 2H),3.63 (m, 3H), 3.39 (dd, J=10.8, 3.4 Hz, 1H), 2.81-2.69 (m, 2H),2.52-2.45 (m, 2H), 2.07 (s, 3H), 1.49-1.41 (m, 2H), 1.18 (s, 6H).

Example 23-(5-((5-chloro-2-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-oxopropanenitrile

Step 1)3-(5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-oxopropanenitrile

To a solution ofN-(2,5-dichloropyrimidin-4-yl)-octahydrocyclopenta[c]pyrrol-5-amine (1.3g, 4.8 mmol), 2-cyanoacetic acid (0.81 g, 9.5 mmol), EDCI (1.8 g, 9.4mmol) and HOAT (1.3 g, 9.6 mmol) in dichloromethane (30 mL) was addedTEA (1.4 g, 14 mmol). The mixture was stirred at room temperature for3.5 h. Then, the mixture was concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/MeOH (v/v)=100/1) togive the title product as a white solid (1.16 g, yield 72%).

LC-MS (ESI, pos. ion) m/z: 340.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.00 (s, 1H), 5.75 (d, J=7.4 Hz, 1H),4.51 (ddd, J=17.4, 7.5, 2.6 Hz, 1H), 3.71-3.58 (m, 3H), 3.50-3.42 (m,3H), 2.90-2.67 (m, 2H), 2.51 (dq, J=14.4, 7.2 Hz, 2H), 1.50-1.37 (m,2H).

Step 2)3-(5-((5-chloro-2-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-oxopropanenitrile

To a solution of 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol (63 mg,0.405 mmol) and3-(5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-oxopropanenitrile(100 mg, 0.293 mmol) in 1,4-dioxane (6 mL) were added cesium carbonate(192 mg, 0.589 mmol), Pd(OAc)₂ (13 mg, 0.057 mmol) and BINAP (39 mg,0.057 mmol). The reaction mixture was stirred at 100° C. overnight andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/30) to give the title compound as ayellow solid (64 mg, yield 47.5%).

LC-MS (ESI, pos. ion) m/z: 459.4 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.87 (s, 1H), 7.73 (s, 1H), 7.61 (s,1H), 6.78 (s, 1H), 5.25 (d, J=6.0 Hz, 1H), 4.41 (d, J=7.4 Hz, 1H), 4.02(s, 2H), 3.66 (d, J=24.5 Hz, 4H), 3.43 (s, 2H), 2.89-2.73 (m, 2H),2.56-2.47 (m, 2H), 1.47-1.42 (m, 2H), 1.19 (s, 6H).

Example 33-(5-((5-chloro-2-((1-(piperidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-oxopropanenitrile

Step 1) tert-butyl 3-hydroxypiperidine-1-carboxylate

To a solution of piperidin-3-ol (1.13 g, 11.2 mmol) and triethylamine(3.05 g, 30.2 mmol) in DCM (20 mL) was added (Boc)₂O (2.60 g, 11.9mmol). The reaction mixture was stirred at rt for 1 h and concentratedin vacuo. The residue was purified by silica gel column chromatography(DCM/MeOH (v/v)=50/1) to give the title compound as light yellow liquid(1.88 g, yield 83.6%).

LC-MS (ESI, pos. ion) m/z: 146.3 [(M+H)−56]⁺.

Step 2) tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate

Under an inert atmosphere, to a solution of 4-nitro-1H-pyrazole (801.2mg, 7.085 mmol), triphenylphosphane (2.79 g, 10.6 mmol) and tert-butyl3-hydroxypiperidine-1-carboxylate (1.64 g, 8.15 mmol) in THF (30 mL) at0° C. was dropwise added a solution of DIAD (2.17 g, 10.7 mmol) in THF(20 mL) in 30 min. The reaction mixture was stirred at 0° C. for 1 hthen stirred at rt for another 18 h and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=10/1) to give the title compound as a white solid (1.92 g, yield91%).

LC-MS (ESI, pos. ion) m/z: 241.3 [M+H−56]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.26 (s, 1H), 8.09 (s, 1H), 4.28-4.20(m, 1H), 4.13 (d, J=10.9 Hz, 1H), 3.79 (dt, J=13.2, 4.3 Hz, 1H),3.51-3.41 (m, 1H), 3.13 (ddd, J=13.3, 9.7, 3.4 Hz, 1H), 2.21-2.13 (m,2H), 1.80-1.70 (m, 1H), 1.65-1.62 (m, 1H), 1.47 (s, 9H).

Step 3) tert-butyl 3-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a solution of tert-butyl3-(4-nitropyrazol-1-yl)piperidine-1-carboxylate (1.08 g, 3.64 mmol) inEtOH (30 mL) was added Pd/C (300 mg, mass %=10%). The reaction mixturewas stirred at rt under H₂ atmosphere for 2.5 h. Filtered, the filtercake was washed with MeOH (150 mL), and the filtrate was concentrated invacuo to give the title compound as yellow oil (860 mg, yield 88%).

LC-MS (ESI, pos. ion) m/z: 267.4 [M+H]⁺.

Step 4) tert-butyl3-(4-((5-chloro-4-((2-(2-cyanoacetyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A mixture of tert-butyl3-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (253.6 mg, 0.9523mmol),3-(5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-oxopropanenitrile(208.7 mg, 0.6135 mmol), Pd(OAc)₂ (14.7 mg, 0.0655 mmol), BINAP (35.4mg, 0.0568 mmol) and cesium carbonate (578.3 mg, 1.775 mmol) weredissolved in 1,4-dioxane (10 mL). The reaction mixture was heated toreflux and stirred for 3 h under an inert atmosphere and thenconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=45/1) to give the title compound as anoff-white solid (86 mg, yield 24.6%).

LC-MS (ESI, pos. ion) m/z: 570.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.87 (s, 1H), 7.73 (s, 1H), 7.57 (s,1H), 6.75 (s, 1H), 5.24 (d, J=7.1 Hz, 1H), 4.49-4.36 (m, 1H), 4.33-4.25(m, 1H), 4.15-4.06 (m, 1H), 4.05-3.94 (m, 1H), 3.74-3.58 (m, 3H),3.47-3.41 (m, 3H), 3.20-3.06 (m, 1H), 2.90-2.74 (m, 3H), 2.57-2.47 (m,2H), 2.26-2.17 (m, 1H), 2.10-1.95 (m, 1H), 1.86-1.75 (m, 2H), 1.47-1.42(m, 11H).

Step 5)3-(5-((5-chloro-2-((1-(piperidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-oxopropanenitrile

tert-butyl3-(4-((5-chloro-4-((2-(2-cyanoacetyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(86 mg, 0.1509 mmol) was dissolved in a solution of HCl in EtOAc (5 mL,3 mmol, 0.5 M) and the reaction mixture was stirred at rt for 30 min.The reaction was quenched with saturated Na₂CO₃ aqueous solution (20mL), extracted with DCM/MeOH (v/v=10/1, 40 mL×6), the combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by preparative TLC (DCM/(a solution ofNH₃ in MeOH (7M) (v/v)=10/1) to give the title compound as a lightyellow solid (20.3 mg, yield 28.6%).

LC-MS (ESI, pos. ion) m/z: 470.4 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃+CD₃OD) δ (ppm): 7.74 (d, J=5.6 Hz, 2H), 7.55 (d,J=3.9 Hz, 1H), 4.65-4.57 (m, 1H), 4.42-4.32 (m, 1H), 3.70-3.56 (m, 3H),3.34-3.23 (m, 6H), 3.02-2.93 (m, 1H), 2.89-2.82 (m, 1H), 2.78-2.70 (m,1H), 2.48-2.39 (m, 2H), 2.16-2.09 (m, 1H), 2.06-2.00 (m, 1H), 1.98-1.90(m, 2H), 1.44-1.34 (m, 2H).

Example 41-(5-((5-chloro-2-((1-(piperidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone

Step 1) tert-butyl3-(4-((4-((2-acetyloctahydrocyclopenta[c]pyrrol-5-yl)amino)-5-chloropyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A mixture of tert-butyl3-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (251.8 mg, 0.9456mmol),1-(5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone(204.3 mg, 0.6482 mmol), Pd(OAc)₂ (14.9 mg, 0.0664 mmol), BINAP (37.6mg, 0.0604 mmol) and cesium carbonate (618.6 mg, 1.899 mmol) wasdissolved in 1,4-dioxane (10 mL). The reaction was heated to reflux andstirred for 3 h under an inert atmosphere and the reaction wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=40/1) to give the title compound as alight yellow solid (185 mg, yield 52.4%).

LC-MS (ESI, pos. ion) m/z: 545.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.85 (s, 1H), 7.74 (s, 1H), 7.57 (s,1H), 6.78 (s, 1H), 5.39 (d, J=7.0 Hz, 1H), 5.11-5.04 (m, 1H), 5.00-4.94(m, 1H), 4.47-4.36 (m, 1H), 4.35-4.24 (m, 1H), 4.14-4.05 (m, 1H),4.05-3.94 (m, 1H), 3.65-3.49 (m, 3H), 3.37 (ddd, J=11.0, 7.6, 3.5 Hz,1H), 3.18-3.07 (m, 1H), 2.86-2.63 (m, 3H), 2.56-2.43 (m, 2H), 2.25-2.17(m, 1H), 2.05 (d, J=3.2 Hz, 3H), 2.03-1.95 (m, 1H), 1.45 (s, 9H),1.38-1.34 (m, 2H).

Step 2)1-(5-((5-chloro-2-((1-(piperidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone

tert-butyl3-(4-((4-((2-acetyloctahydrocyclopenta[c]pyrrol-5-yl)amino)-5-chloropyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(185 mg, 0.3394 mmol) was dissolved in a solution of HCl in EtOAc (6 mL,3 mmol, 0.5 M) and the reaction mixture was stirred at rt for 30 min.The reaction mixture was washed with water (20 mL×2), and the combinedaqueous phases were adjusted to pH=10 with Na₂CO₃ power and thenextracted with DCM/MeOH (v/v=10/1, 50 mL×6). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by a preparative TLC (DCM/(a solution of NH₃ inMeOH (7M)) (v/v)=10/1) to give the title compound as a light yellowsolid (68.3 mg, yield 45.2%).

LC-MS (ESI, pos. ion) m/z: 445.4 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.86 (s, 1H), 7.79 (s, 1H), 7.57 (s,1H), 6.81 (s, 1H), 5.25 (d, J=7.1 Hz, 1H), 4.52-4.35 (m, 2H), 3.68-3.58(m, 3H), 3.55 (dd, J=12.5, 3.2 Hz, 1H), 3.39 (dd, J=10.9, 3.3 Hz, 1H),3.32-3.22 (m, 2H), 2.98-2.90 (m, 1H), 2.83-2.70 (m, 2H), 2.54-2.43 (m,2H), 2.26-2.18 (m, 1H), 2.11-2.03 (m, 4H), 1.96-1.82 (m, 2H), 1.49-1.38(m, 2H).

Example 53-(5-((5-chloro-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-oxopropanenitrile

Step 1) tert-butyl 4-hydroxypiperidine-1-carboxylate

To a solution of piperidin-4-ol (2 g, 19.773 mmol) and TEA (4 g, 39.530mmol) in tetrahydrofuran (20 mL) were dropwise added (Boc)₂O (5.2 g, 24mmol). The mixture was stirred at rt overnight and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EA (v/v)=10/1 to 5/1) to give the title product as a white solid(3.91 g, yield 98.3%).

LC-MS (ESI, pos. ion) m/z: 146.1 [M−55]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 3.82 (d, J=8.4 Hz, 3H), 3.01 (ddd,J=13.3, 9.8, 3.2 Hz, 2H), 1.92 (s, 1H), 1.83 (dd, J=11.0, 5.5 Hz, 3H),1.44 (s, 9H).

Step 2) tert-butyl 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1 g,4.9687 mmol), 4-nitro-1H-pyrazole (675 mg, 5.9692 mmol) andtriphenylphosphane (1.96 g, 7.47 mmol) in anhydrous THF (50 mL) wasdropwise added DIAD (1.5 mL, 7.6 mmol) at 0° C. for 30 min. The reactionmixture was stirred at rt for 1 h, and then moved to rt overnight. Theresulting mixture was concentrated in vacuo, and the residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=20/1 to4/1) to give the title product as a white solid (1.35 g, yield 91.7%).

LC-MS (ESI, pos. ion) m/z: 241.2 [M−55]⁺.

Step 3) tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.35 g, 4.56 mmol)in ethanol (30 mL) was added Pd/C (135 mg, 1.269 mmol, mass %=10%). Themixture was stirred under a H₂ atmosphere at rt for 2 h. The resultingmixture was filtered and the filtrate was concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=50/1 to 25/1) to give the title product as brown oil (955 mg,yield 78.7%).

LC-MS (ESI, pos. ion) m/z: 211.1 [M−55]⁺.

Step 4) tert-butyl4-(4-((5-chloro-4-((2-(2-cyanoacetyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a solution of3-(5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-oxopropanenitrile(350 mg, 1.029 mmol), tert-butyl4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (411 mg, 1.543 mmol)and cesium carbonate (1.1 g, 3.4 mmol) in 1,4-dioxane (25 mL) were addedPd(OAc)₂ (23.1 mg, 0.103 mmol) and BINAP (64.1 mg, 0.103 mmol). Thereaction mixture was degassed for 2 min and refilled with N₂ and thenstirred at 105° C. for 2 h. The mixture was concentrated in vacuo andthe residue was purified by silica gel column chromatography (DCM/MeOH(v/v)=50/1 to 25/1) to give the title compound as a light yellow solid(254 mg, yield 43.31%).

LC-MS (ESI, pos. ion) m/z: 570.3 [M+H]⁺.

Step 5)3-(5-((5-chloro-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-oxopropanenitrile

To a solution of tert-butyl4-(4-((5-chloro-4-((2-(2-cyanoacetyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(254 mg, 0.4455 mmol) in dichloromethane (12 mL) was added a solution ofHCl in EtOAc (6 mL, 24 mmol, 4M). The reaction mixture was stirred at rtfor 30 min and concentrated in vacuo. The residue was dissolved in water(20 mL) and the resulting solution was adjusted to pH=8-9 with saturatedNaHCO₃ aqueous solution, then extracted with DCM/MeOH (v/v=10/1, 50mL×6). The combined organic phases were washed with brine (100 mL),dried over anhydrous Na₂SO₄, then filtered and concentrated in vacuo.The residue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/10) to give the title compound as a light yellow solid (77 mg,yield 36.77%).

LC-MS (ESI, pos. ion) m/z: 470.5 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.04 (s, 1H), 7.86 (s, 1H), 7.83 (s,1H), 7.45 (s, 1H), 6.91 (d, J=7.6 Hz, 1H), 4.49 (dd, J=15.6, 7.8 Hz,1H), 4.21 (t, J=11.3 Hz, 1H), 3.93 (s, 2H), 3.39 (d, J=6.2 Hz, 2H), 3.14(d, J=17.7 Hz, 4H), 2.71 (dd, J=34.0, 23.2 Hz, 4H), 2.24 (dd, J=12.0,6.3 Hz, 2H), 2.01 (d, J=11.4 Hz, 2H), 1.84 (dd, J=20.6, 11.5 Hz, 2H),1.53 (dd, J=13.9, 7.9 Hz, 2H).

Example 61-(5-((5-chloro-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone

Step 1) tert-butyl4-(4-((4-((2-acetyloctahydrocyclopenta[c]pyrrol-5-yl)amino)-5-chloropyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a solution of1-(5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone(350 mg, 1.110 mmol), tert-butyl4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (443.6 mg, 1.666mmol) and cesium carbonate (1.1 g, 3.4 mmol) in 1,4-dioxane (25 mL) wereadded Pd(OAc)₂ (25 mg, 0.1114 mmol) and BINAP (69.2 mg, 0.111 mmol). Themixture was degassed for 2 min and refilled with N₂. The reactionmixture was stirred at 105° C. for 2 h and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=50/1 to 25/1) to give the title compound as a light yellow solid(585 mg, yield 96.65%).

LC-MS (ESI, pos. ion) m/z: 545.5 [M+H]⁺.

Step 2)1-(5-((5-chloro-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone

To a solution of tert-butyl4-(4-((4-((2-acetyloctahydrocyclopenta[c]pyrrol-5-yl)amino)-5-chloropyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(585 mg, 1.073 mmol) in dichloromethane (12 mL) was added a solution ofHCl in EtOAc (6 mL, 24 mmol, 4M). The reaction mixture was stirred at rtfor 30 min and concentrated in vacuo. The residue was dissolved in water(20 mL), and the resulting solution was adjusted to pH=8-9 with asaturated NaHCO₃ aqueous solution, then extracted with DCM/MeOH(v/v=10/1, 50 mL×6). The combined organic phases were washed with brine(100 mL), dried over anhydrous Na₂SO₄, then filtered and concentrated invacuo. The residue was purified by silica gel column chromatography(MeOH/DCM (v/v)=1/10) to give the title compound as an off white solid(375 mg, yield 78.52%).

LC-MS (ESI, pos. ion) m/z: 445.4 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.04 (s, 1H), 7.86 (s, 1H), 7.84 (s,1H), 7.45 (s, 1H), 6.94 (d, J=7.7 Hz, 1H), 4.49 (td, J=9.8, 2.1 Hz, 1H),4.18 (td, J=11.3, 5.7 Hz, 1H), 3.41 (dd, J=8.8, 5.2 Hz, 4H), 3.12 (d,J=12.6 Hz, 2H), 2.71 (t, J=11.3 Hz, 3H), 2.64-2.53 (m, 1H), 2.24 (dd,J=12.0, 5.8 Hz, 2H), 2.00 (d, J=10.8 Hz, 2H), 1.95 (s, 3H), 1.82 (tt,J=11.8, 6.1 Hz, 2H), 1.59-1.45 (m, 2H).

Example 73-(5-((5-chloro-2-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-oxopropanenitrile

Step 1) 2-(4-nitro-1H-pyrazol-1-yl)pyridine

To a solution of 4-nitro-1H-pyrazole (2.01 g, 17.7 mmol) and2-iodopyridine (4.37 g, 21.3 mmol) in DMF (20 mL) were added iodocopper(674 mg, 3.54 mmol), cesium carbonate (11.6 g, 35.5 mmol) andcyclohexane-1,2-diamine (407 mg, 3.56 mmol) and then the reactionmixture was stirred at 100° C. for 4 h. The reaction was quenched withwater (100 mL) and extracted with EtOAc (250 mL×3). The combined organicphases were washed with brine (100 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (EtOAc/PE (v/v)=1/15) to give the titlecompound as a white solid (1.8 g, 53.6%).

LC-MS (ESI, pos. ion) m/z: 191.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.28 (s, 1H), 8.51-8.47 (m, 1H), 8.26(s, 1H), 8.06-8.02 (m, 1H), 7.94-7.88 (m, 1H), 7.37-7.33 (m, 1H).

Step 2) 1-(pyridin-2-yl)-1H-pyrazol-4-amine

To a solution of 2-(4-nitro-1H-pyrazol-1-yl)pyridine (1.52 g, 8.21 mmol)in MeOH (80 mL) was added Pd/C (210 mg, mass %=10%). The reactionmixture was stirred at rt in a high pressure autoclave under 2 MPa H₂atmosphere overnight and filtered. The filtrate was concentrated invacuo to give the title compound as purple oil (1.62 g, yield 98.6%).

LC-MS (ESI, pos. ion) m/z: 161.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.35 (d, J=3.9 Hz, 1H), 8.09 (d, J=0.4Hz, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.78-7.72 (m, 1H), 7.41 (s, 1H),7.13-7.08 (m, 1H), 3.10 (s, 2H).

Step 3) tert-butyl5-((5-chloro-2-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a solution of tert-butyl5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(501 mg, 1.34 mmol) and 1-(pyridin-2-yl)-1H-pyrazol-4-amine (259 mg,1.62 mmol) in 1,4-dioxane (20 mL) were added Pd(OAc)₂ (60 mg, 0.267mmol), BINAP (167 mg, 0.268 mmol) and caesium carbonate (872 mg, 2.67mmol). The reaction mixture was stirred at 108° C. overnight andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (EtOAc/PE (v/v)=1/3) to give the title compound as ayellow solid (589 mg, yield 88.3%).

LC-MS (ESI, pos. ion) m/z: 497.4 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.91 (s, 1H), 8.35 (d, J=4.5 Hz, 1H),7.95 (d, J=8.3 Hz, 1H), 7.90 (s, 1H), 7.81-7.75 (m, 2H), 7.17-7.12 (m,1H), 6.85 (s, 1H), 5.35-5.31 (m, 1H), 4.54-4.50 (m, 1H), 3.51-3.38 (m,4H), 2.80-2.78 (m, 2H), 2.60-2.51 (m, 2H), 1.47 (s, 9H), 1.44-1.39 (m,2H).

Step 4)5-chloro-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)-N²-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

To a solution of5-((5-chloro-2-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(589 mg, 1.19 mmol) in dichloromethane (20 mL) was added a solution ofHCl in EtOAc (10 mL, 30 mmol, 3 M). The reaction mixture was stirred atrt overnight and concentrated in vacuo. The residue was dissolved inEtOAc (20 mL), and the resulting solution was adjusted to pH=10 with asaturated NaHCO₃ aqueous solution, then extracted with EtOAc (50 mL×3).The combined organic phases were washed with brine (50 mL×3), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound as a yellow solid (400 mg, yield 85.1%).

LC-MS (ESI, pos. ion) m/z: 397.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.85 (s, 1H), 8.37 (d, J=3.8 Hz, 1H),7.94 (d, J=8.3 Hz, 1H), 7.84 (d, J=9.0 Hz, 2H), 7.80-7.75 (m, 1H), 7.59(d, J=9.0 Hz, 1H), 7.16-7.12 (m, 1H), 6.68 (s, 1H), 4.61-4.56 (m, 1H),2.89-2.87 (m, 4H), 2.74-2.72 (m, 2H), 2.38-2.32 (m, 2H), 1.49-1.44 (m,2H).

Step 5)3-(5-((5-chloro-2-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-oxopropanenitrile

To a solution of5-chloro-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)-N²-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine(100 mg, 0.252 mmol) and 2-cyanoacetic acid (25 mg, 0.294 mmol) indichloromethane (5 mL) were added EDCI (97 mg, 0.506 mmol), HOAT (68 mg,0.501 mmol) and Et₃N (54 mg, 0.533 mmol). The reaction mixture wasstirred at rt for 6 h and concentrated in vacuo. The residue waspurified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) togive the title compound as a white solid (50.1 mg, yield 72.8%).

LC-MS (ESI, pos. ion) m/z: 464.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.41 (s, 1H), 8.91 (s, 1H), 8.42 (d,J=4.1 Hz, 1H), 7.96 (d, J=6.4 Hz, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.78 (s,1H), 7.31-7.26 (m, 1H), 7.09 (s, 1H), 4.60-4.57 (m, 1H), 3.94 (s, 2H),3.65-3.48 (m, 3H), 3.46-3.41 (m, 2H), 2.76-2.72 (m, 2H), 2.35-2.31 (m,2H), 1.58-1.51 (m, 2H).

Example 81-(5-((5-chloro-2-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone

To a solution of5-chloro-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)-N²-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine(100 mg, 0.252 mmol) and acetic anhydride (31 mg, 0.304 mmol) indichloromethane (5 mL) was added triethylamine (57 mg, 0.563 mmol). Thereaction mixture was stirred at rt overnight and concentrated in vacuo.The residue was purified by preparative TLC (MeOH/DCM (v/v)=1/20) toafford the title compound as a yellow solid (80 mg, yield 72.3%).

LC-MS (ESI, pos. ion) m/z: 439.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.91 (s, 1H), 8.34 (d, J=4.0 Hz, 1H),7.96 (d, J=8.3 Hz, 1H), 7.90 (s, 1H), 7.82-7.76 (m, 2H), 7.17-7.13 (m,1H), 6.96 (s, 1H), 5.32-5.28 (m, 1H), 4.57-4.53 (m, 1H), 3.69-3.61 (m,3H), 3.44-3.39 (m, 1H), 2.94-2.80 (m, 2H), 2.65-2.59 (m, 2H), 2.08 (s,3H), 1.48-1.41 (m, 2H).

Example 95-chloro-N²-(1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine

Step 1) 2-chloro-5-(4-nitro-1H-pyrazol-1-yl)pyridine

To s suspension of 3-nitro-1H-pyrazole (2.50 g, 22.11 mmol) in anhydrousDMF (80.0 mL) were added 2-chloro-5-iodopyridine (6.36 g, 26.55 mmol),iodocopper (0.85 g, 4.47 mmol, cyclohexane-1,2-diamine (0.52 g, 4.54mmol) and cesium carbonate (14.54 g, 44.62 mmol). The reaction mixturewas degassed for 2 min and refilled with N₂ and stirred at 100° C.overnight. Then the mixture was diluted with EtOAc (100 mL), filteredand washed with MeOH (550 mL). The filtrate was concentrated in vacuo.The residue was purified by silica gel column chromatography (EA/PE(v/v)=1/4 to 1/2) to afford the title compound as a light yellow solid(0.36 g, yield 7%).

LC-MS (ESI, pos. ion) m/z: 225.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.80 (d, J=2.8 Hz, 1H), 8.66 (s, 1H),8.32 (s, 1H), 8.07 (dd, J=8.6, 2.9 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H).

Step 2) 2-methoxy-5-(4-nitro-1H-pyrazol-1-yl)pyridine

To a suspension of 2-chloro-5-(4-nitro-1H-pyrazol-1-yl)pyridine (0.36 g,1.60 mmol) in MeOH (15.0 mL) was added a solution of sodium methanolatein MeOH (5.0 mL, 25.0 mmol, 5 M). The reaction mixture was heated to 50°C. and stirred for 12 h and concentrated in vacuo. The residue wasdiluted with water (15.0 mL), and then filtered. The filter cake waswashed with water (5.0 mL) and the filtrate was extracted with DCM (20mL×3). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue and the filter cake wascombined and dried in vacuo to afford the title compound as a yellowsolid (0.32 g, yield 91%).

LC-MS (ESI, pos. ion) m/z: 221.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.53 (s, 1H), 8.49 (d, J=2.7 Hz, 1H),8.27 (s, 1H), 7.92 (dd, J=8.9, 2.8 Hz, 1H), 6.90 (d, J=8.9 Hz, 1H), 4.00(s, 3H).

Step 3) 1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-amine

To a suspension of 2-methoxy-5-(4-nitro-1H-pyrazol-1-yl)pyridine (0.32g, 1.50 mmol) in MeOH (10.0 mL) was added Pd/C (0.067 g, mass %=10%).The reaction mixture was stirred at room temperature for 1 h under H₂atmosphere and then filtered. The filter cake was washed with MeOH (10.0mL) and the filtrate was concentrated in vacuo. The residue was purifiedby silica gel column chromatography (EtOAc/PE (v/v)=1/1 to DCM/(asolution of NH₃ in MeOH (3M) (v/v)=20/1) to afford the title compound asa black solid (0.15 g, yield 54%).

LC-MS (ESI, pos. ion) m/z: 191.3 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.48 (d, J=2.7 Hz, 1H), 8.02 (dd,J=8.9, 2.8 Hz, 1H), 7.66 (s, 1H), 7.26 (s, 1H), 6.90 (d, J=8.9 Hz, 1H),4.17 (s, 2H), 3.87 (s, 3H).

Step 4) tert-butyl5-((5-chloro-2-((1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a suspension of tert-butyl 5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.30 g, 0.81 mmol) inanhydrous 1,4-dioxane (10.0 mL) were added1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-amine (0.15 g, 0.79 mmol),Pd(OAc)₂ (0.037 g, 0.17 mmol), BINAP (0.10 g, 0.16 mmol) and cesiumcarbonate (0.53 g, 1.64 mmol). The mixture was degassed for 2 min andrefilled with N₂, then and heated to 100° C. and stirred overnight. Themixture was concentrated in vacuo and the residue was purified by silicachromatography (EtOAc/PE (v/v)=1/2 to 2/1) to afford the title compoundas a yellow solid (0.24 g, yield 57%).

LC-MS (ESI, pos. ion) m/z: 527.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.43 (d, J=2.6 Hz, 1H), 8.23 (s, 1H),7.93 (dd, J=8.9, 2.8 Hz, 1H), 7.90 (s, 1H), 7.75 (s, 1H), 6.83 (d, J=8.9Hz, 1H), 6.80 (s, 1H), 5.34 (d, J=7.1 Hz, 1H), 4.48-4.35 (m, 1H), 3.97(s, 3H), 3.53-3.45 (m, 2H), 3.43-3.33 (m, 2H), 2.74-2.65 (m, 2H),2.52-2.41 (m, 2H), 1.48-1.45 (m, 11H).

Step 5)5-chloro-N²-(1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine

To a suspension of tert-butyl5-((5-chloro-2-((1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(0.24 g, 0.46 mmol) in DCM (10.0 mL) was added a solution of HCl inEtOAc (10.0 mL, 3 M). The reaction mixture was stirred at roomtemperature for 30 min and then concentrated in vacuo. The residue wasdiluted with DCM (10 mL) and saturated Na₂CO₃ aqueous solution (10 mL)and the resulting mixture was stirred for another 15 min. The resultingmixture was extracted with DCM (20 mL×3) and DCM/MeOH (v/v)=10/1, 20mL×3). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (DCM/(a solution of NH₃ in MeOH (3M))(v/v)=50/1 to 25/1) to afford the title compound as a yellow solid (0.17g, yield 87%).

LC-MS (ESI, pos. ion) m/z: 427.4 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.25 (s, 1H), 8.53 (d, J=2.6 Hz, 1H),8.38 (s, 1H), 8.06 (dd, J=8.9, 2.8 Hz, 1H), 7.90 (s, 1H), 7.78 (s, 2H),6.95 (d, J=8.9 Hz, 1H), 4.53-4.41 (m, 1H), 3.89 (s, 3H), 2.89-2.82 (m,2H), 2.82-2.74 (m, 2H), 2.64-2.55 (m, 2H), 2.27-2.15 (m, 2H), 1.53-1.40(m, 2H).

Example 103-(5-((5-chloro-2-((1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-oxopropanenitrile

To a suspension of5-chloro-N²-(1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(75 mg, 0.18 mmol) in anhydrous DCM (2.0 mL) were added 2-cyanoaceticacid (0.004 g, 0.045 mmol), EDCI (0.007 g, 0.037 mmol), HOAT (0.006 g,0.043 mmol) and Et₃N (0.005 g, 0.051 mmol). The reaction mixture wasstirred at room temperature for 30 min. The mixture was diluted with DCM(30 mL), washed with water (10 mL×2), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (DCM/(a solution of NH₃ in MeOH (3M))(v/v)=100/1 to 50/1) to afford the title compound as a light yellowsolid (75 mg, yield 86%).

LC-MS (ESI, pos. ion) m/z: 494.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.42 (d, J=2.7 Hz, 1H), 8.20 (s, 1H),7.96-7.90 (m, 2H), 7.77 (s, 1H), 6.86-6.81 (m, 2H), 5.29 (d, J=7.1 Hz,1H), 4.51-4.38 (m, 1H), 3.97 (s, 3H), 3.75-3.64 (m, 3H), 3.49-3.43 (m,3H), 2.92-2.71 (m, 2H), 2.61-2.48 (m, 2H), 1.55-1.41 (m, 2H).

Example 111-(5-((5-chloro-2-((1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone

To a suspension of5-chloro-N²-(1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(0.050 g, 0.12 mmol) in DCM (3.0 mL) were added Et₃N (0.020 g, 0.19mmol) and acetyl acetate (0.015 g, 0.15 mmol). The reaction mixture wasstirred at room temperature for 30 min and then concentrated in vacuo.The residue was purified by silica gel column chromatography (DCM/(asolution of NH₃ in MeOH (3M)) (v/v)=100/1 to 50/1) to afford the titlecompound as a white solid (37 mg, yield 67%).

LC-MS (ESI, pos. ion) m/z: 469.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.42 (d, J=2.6 Hz, 1H), 8.21 (s, 1H),7.93 (dd, J=9.0, 2.8 Hz, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 6.86-6.81 (m,2H), 5.28 (d, J=7.1 Hz, 1H), 4.50-4.37 (m, 1H), 3.97 (s, 3H), 3.67-3.59(m, 3H), 3.44-3.37 (m, 1H), 2.83-2.69 (m, 2H), 2.57-2.46 (m, 2H), 2.07(s, 3H), 1.50-1.43 (m, 2H).

Example 121-(5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-2-cyclopropylethanone

Step 1) tert-butyl5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a suspension of tert-butyl5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(579.6 mg, 1.55 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride(213.0 mg, 1.34 mmol) in n-BuOH (5 mL) was added N-ethyldiisopropylamine(668.2 mg, 5.17 mmol). The reaction mixture was stirred at 150° C. in asealed tube overnight and concentrated in vacuo. The residue waspurified by silica gel column chromatography (MeOH/DCM (v/v)=1/80) togive the title compound as a beige solid (672.6 mg, yield 100%).

LC-MS (ESI, pos. ion) m/z: 434.3 [M+H]⁺.

Step 2)5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine

To a solution of tert-butyl5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(672.6 mg, 1.55 mmol) in DCM (10 mL) was added a solution of HCl inEtOAc (10 mL, 40 mmol). The reaction mixture was stirred at rt overnightand concentrated in vacuo. The residue was dissolved in water (30 mL),and the resulting solution was adjusted to pH=10 with saturated Na₂CO₃aqueous solution, then extracted with DCM (250 mL×3). The combinedorganic phases were washed with brine (250 mL), dried over anhydrousNa₂SO₄, then filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (MeOH/DCM (v/v)=1/5) togive the title compound as a beige solid (410 mg, yield 79.2%).

LC-MS (ESI, pos. ion) m/z: 334.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.01 (s, 1H), 7.88 (s, 1H), 7.66 (s,1H), 7.55 (s, 1H), 6.70 (s, 1H), 5.54 (s, 1H), 4.40 (m, 1H), 3.89 (s,3H), 3.39 (d, J=11.6 Hz, 2H), 3.29 (m, 2H), 2.94 (m, 2H), 2.51 (m, 2H),1.83 (m, 2H).

Step 3)1-(5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-2-cyclopropylethanone

To a solution of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(101.0 mg, 0.30 mmol) and 2-cyclopropylacetic acid (64.6 mg, 0.64 mmol)in DCM (15 mL) were added HOAT (89.2 mg, 0.66 mmol), EDCI (122.4 mg,0.63 mmol) and Et₃N (104.0 mg, 1.03 mmol). The reaction mixture wasstirred at rt for 0.5 h, then quenched with H₂O (30 mL) and extractedwith DCM (100 mL×3). The combined organic phases were washed with brine(100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by silica gel column chromatography(MeOH/DCM (v/v)=1/30) to give the title compound as a beige solid (83.2mg, yield 66.1%).

LC-MS (ESI, pos. ion) m/z: 416.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.89 (s, 1H), 7.68 (s, 1H), 7.56 (s,1H), 6.71 (s, 1H), 5.25 (d, J=7.2 Hz, 1H), 4.42 (m, 1H), 3.90 (s, 3H),3.65 (d, J=6.2 Hz, 2H), 3.61 (m, 1H), 3.41 (dd, J=10.8, 3.2 Hz, 1H),2.78 (m, 2H), 2.50 (td, J=15.8, 7.9 Hz, 2H), 2.25 (m, 2H), 1.45 (m, 2H),1.11 (m, 1H), 0.59 (q, J=5.4 Hz, 2H), 0.19 (q, J=5.0 Hz, 2H).

Example 135-chloro-N⁴-(2-(cyclopropylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)-N²-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

Under the protection of nitrogen, to a suspension of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(60 mg, 0.18 mmol) and triethylamine (28 mg, 0.28 mmol) in a mixture ofanhydrous DCM (10.0 mL) and DMF (0.50 mL) was added cyclopropanesulfonylchloride (31 mg, 0.22 mmol). The reaction mixture was stirred at roomtemperature overnight and then concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/MeOH (v/v)=50/1 to30/1 to 20/1) to afford the title compound as a white solid (31 mg,yield 39%).

LC-MS (ESI, pos, ion) m/z: 438.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.89 (s, 1H), 7.67 (s, 1H), 7.54 (s,1H), 6.58 (s, 1H), 5.38 (d, J=7.5 Hz, 1H), 4.42-4.29 (m, 1H), 3.90 (s,3H), 3.42-3.29 (m, 4H), 2.83-2.74 (m, 2H), 2.54-2.45 (m, 2H), 2.42-2.33(m, 1H), 1.55-1.45 (m, 2H), 1.26-1.20 (m, 2H), 1.07-0.99 (m, 2H).

Example 14(5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(cyclopropyl)methanone

To a solution of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(70 mg, 0.210 mmol) and triethylamine (35 mg, 0.346 mmol) indichloromethane (5 mL) was added cyclopropanecarbonyl chloride (27 mg,0.258 mmol). The reaction mixture was stirred at rt for 20 min andconcentrated in vacuo. The residue was purified by preparative TLC(MeOH/DCM (v/v)=1/20) to afford the title compound as a yellow solid (26mg, yield 30.9%).

LC-MS (ESI, pos. ion) m/z: 402.1 [M+H]⁺;

1H NMR (400 MHz, CDCl₃) δ (ppm): 7.87 (s, 1H), 7.66 (s, 1H), 7.53 (s,1H), 6.69 (s, 1H), 5.25 (d, J=7.1 Hz, 1H), 4.46-4.38 (m, 1H), 3.88 (s,3H), 3.84-3.77 (m, 1H), 3.63 (d, J=6.6 Hz, 2H), 2.83-2.69 (m, 2H),2.53-2.44 (m, 2H), 1.69-1.58 (m, 4H), 1.01 (t, J=3.6 Hz, 2H), 0.79-0.74(m, 2H).

Example 15 ethyl5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a solution of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(71 mg, 0.213 mmol) and triethylamine (35 mg, 0.346 mmol) in DCM (5 mL)was added ethyl carbonochloridate (27 mg, 0.249 mmol). The reactionmixture was stirred at rt for 20 min and concentrated in vacuo. Theresidue was purified by preparative TLC (MeOH/DCM (v/v)=1/20) to affordthe title compound as a yellow solid (22 mg, yield 25.5%).

LC-MS (ESI, pos. ion) m/z: 406.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.86 (s, 1H), 7.66 (s, 1H), 7.51 (s,1H), 6.60 (s, 1H), 5.26 (d, 1H), 4.39 (m, 9.2 Hz, 1H), 4.14 (q, 2H),3.87 (s, 3H), 3.47 (d, 4H), 2.74-2.67 (m, 2H), 2.50-2.41 (m, 2H),1.46-1.40 (m, 2H), 1.26 (s, 3H).

Example 161-(5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-2-methylpropan-2-ol

To a solution of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(118.9 mg, 0.36 mmol) in MeOH (10 mL) was added 2,2-dimethyloxirane(44.1 mg, 0.61 mmol). The reaction mixture was stirred at 80° C. in asealed tube overnight, then cooled down to rt and concentrated in vacuo.The residue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/10) to give the title compound as a beige solid (107.9 mg, yield74.6%).

LC-MS (ESI, pos. ion) m/z: 406.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃ and MeOH-d₄) δ (ppm): 7.75 (s, 1H), 7.64 (s, 1H),7.53 (s, 1H), 4.33 (m, 1H), 3.83 (s, 3H), 3.33 (m, 2H), 2.94 (d, J=9.3Hz, 2H), 2.74 (m, 1H), 2.67 (m, 1H), 2.63 (s, 2H), 2.38 (dt, J=12.9, 6.6Hz, 2H), 1.49 (m, 2H), 1.24 (s, 6H).

Example 175-chloro-N⁴-(2-((cyclopropylmethyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)-N²-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

Step 1) Sodium Cyclopropyl Methanesulfonate

To the solid of (bromomethyl)cyclopropane (2.0 g, 14.83 mmol) was addedsaturated Na₂SO₃ aqueous solution (20.0 mL). The reaction mixture washeated to reflux and stirred for 24 h and concentrated in vacuo. To theresidue was added EtOH (30 mL), and the mixture was stirred at 50° C.for 30 min, then filtered immediately. The filtrate was concentrated invacuo and the residue was diluted with toluene (20 mL), and thenconcentrated in vacuo again. The residue was dried in vacuo to affordthe title compound as a white solid (1.25 g, yield 53%).

LC-MS (ESI, neg. ion) m/z: 135.1 [M−Na]⁻;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 2.34 (d, J=6.5 Hz, 2H), 0.99-0.89 (m,1H), 0.45-0.33 (m, 2H), 0.19-0.09 (m, 2H).

Step 2) Cyclopropylmethanesulfonyl Chloride

To a suspension of sodium cyclopropylmethanesulfonate (0.48 g, 3.04mmol) in anhydrous THF (10.0 mL) were added DMF (0.26 mL, 3.40 mmol) andthionyl chloride (0.73 g, 6.15 mmol). The reaction mixture was heated toreflux and stirred for 3 h, then cooled down to room temperature andfiltered. The filtrate was concentrated in vacuo to afford the titlecompound as brown liquid (0.47 g, 100%). The crude product was used fornext reaction without further purification.

Step 3)5-chloro-N⁴-(2-((cyclopropylmethyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)-N²-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

Under the protection of nitrogen, to a suspension of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(0.20 g, 0.60 mmol) and triethylamine (0.20 mL, 1.40 mmol) in anhydrousDCM (20.0 mL) was added cyclopropylmethanesulfonyl chloride (0.14 g,0.91 mmol) slowly. The reaction mixture was stirred at room temperaturefor 2 h and concentrated in vacuo. The residue was purified by silicagel column chromatography (DCM/(a solution of NH₃ in MeOH) (3M)(v/v)=50/1 to 30/1) to afford the title compound as a light yellow solid(50 mg, yield 18%).

LC-MS (ESI, pos. ion) m/z: 452.2 [M+H]⁺;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 7.87 (s, 1H), 7.65 (s, 1H), 7.52 (s,1H), 6.58 (s, 1H), 5.29 (d, J=5.8 Hz, 1H), 4.35-4.27 (m, 1H), 3.88 (s,3H), 3.44-3.37 (m, 2H), 3.36-3.30 (m, 2H), 2.94 (d, J=7.1 Hz, 2H),2.77-2.70 (m, 2H), 2.51-2.44 (m, 2H), 1.50-1.44 (m, 2H), 1.19-1.13 (m,1H), 0.76-0.70 (m, 2H), 0.41-0.35 (m, 2H).

Example 185-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-ethylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

To a solution of phenyl carbonochloridate (506.5 mg, 3.235 mmol) at 0°C. was dropwise added a solution of ethanamine in THF (6 mL, 12 mmol, 2M). The reaction mixture was stirred at rt for 10 min. The reaction wasquenched with H₂O (20 mL), extracted with EtOAc (30 mL×3). The combinedorganic phases were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give phenyl ethylcarbamate as a colorlessliquid. To the solution of phenyl ethylcarbamate in DCM (20 mL) wereadded N,N-diethylethanamine (162.8 mg, 1.609 mmol) and5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(107.6 mg, 0.3223 mmol). The reaction mixture was stirred at rtovernight and then concentrated in vacuo. The residue was purified bysilica gel column chromatography (DCM/MeOH (v/v)=15/1) to give the titlecompound as a white solid (95 mg, yield 59%).

LC-MS (ESI, pos. ion) m/z: 405.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.85 (s, 1H), 7.66 (s, 1H), 7.52 (s,1H), 6.72 (s, 1H), 5.36 (d, J=7.2 Hz, 1H), 4.42 (dd, J=15.3, 7.7 Hz,1H), 4.18-4.26 (m, 1H), 3.87 (s, 3H), 3.48 (dd, J=10.1, 7.5 Hz, 2H),3.37-3.23 (m, 4H), 2.79-2.69 (m, 2H), 2.49-2.38 (m, 2H), 1.53-1.41 (m,2H), 1.15 (t, J=7.2 Hz, 3H).

Example 195-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-cyclopropylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

Step 1) Phenyl Cyclopropylcarbamate

To a suspension of phenyl carbonochloridate (2.00 g, 12.78 mmol) andtriethylamine (3.60 mL, 25.08 mmol) in anhydrous DCM (20.0 mL) was addedcyclopropanamine (1.10 g, 19.24 mmol) slowly at 0° C. The reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with DCM (50 mL), washed with water (40 mL×2) and brine (40 mL).The separated organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by silica gel columnchromatography (EtOAc/PE (v/v)=1/20 to 1/10) to afford the titlecompound as a white solid (0.85 g, yield 38%).

LC-MS (ESI, pos. ion) m/z: 178.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.40-7.31 (m, 2H), 7.23-7.16 (m, 1H),7.16-7.08 (m, 2H), 5.22 (s, 1H), 2.81-2.63 (m, 1H), 0.83-0.75 (m, 2H),0.67-0.59 (m, 2H).

Step 2)5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-cyclopropylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

To a suspension of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(0.10 g, 0.30 mmol) in THF (5.0 mL) were added phenylcyclopropylcarbamate (0.12 g, 0.68 mmol) and triethylamine (0.15 mL,1.10 mmol). The mixture was heated to reflux and stirred for 24 h, andthen concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/(a solution of NH₃ in MeOH) (3M) (v/v)=100/1to 50/1 to 30/1) to afford the title compound as a light yellow solid(50 mg, yield 40%).

LC-MS (ESI, pos. ion) m/z: 417.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.86 (s, 1H), 7.65 (s, 1H), 7.52 (s,1H), 6.64 (s, 1H), 5.33 (d, J=7.2 Hz, 1H), 4.49 (s, 1H), 4.47-4.35 (m,1H), 3.87 (s, 3H), 3.50-3.43 (m, 2H), 3.35-3.29 (m, 2H), 2.78-2.70 (m,2H), 2.68-2.62 (m, 1H), 2.48-2.39 (m, 2H), 1.52-1.43 (m, 2H), 0.75-0.70(m, 2H), 0.50-0.45 (m, 2H).

Example 201-(9-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecan-3-yl)-2-cyclopropylethanone

Step 1) tert-butyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate

To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (10.0 g,46.9 mmol) and KOH (1.3 g, 23.5 mmol) in EtOH (200 mL) was addedbut-3-en-2-one (3.9 g, 56.3 mmol), the mixture was stirred at 70° C. for16 h and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (EtOAc/PE (v/v)=1/4) to give the product as brownoil (5.2 g, yield 41.8%).

LC-MS (ESI, pos. ion) m/z: 210.2 [M−55]⁺.

Step 2) tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate

To a solution of tert-butyl9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (5.2 g, 19.6 mmol) in DCM(80 mL) was added Pd/C (0.5 g, mass %=10%) and the suspension wasstirred at room temperature under a H₂ atmosphere overnight. Thereaction mixture was filtered and concentrated in vacuo, then theresidue was purified by silica gel column chromatography (EtOAc/PE(v/v)=1/4) to give the product as brown oil (3.1 g, yield 59.0%).

LC-MS (ESI, pos. ion) m/z: 212.1 [M−55]⁺.

Step 3) tert-butyl 9-amino-3-azaspiro[5.5]undecane-3-carboxylate

To a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate(5.35 g, 20.0 mmol) in EtOH (40 mL) were added a solution of NH₃ in MeOH(7M, 40 mL, 280.0 mmol) and Ti(Oi-Pr)₄ (11.30 g, 40.0 mmol), the mixturewas stirred at room temperature overnight. And then NaBH₄ (1.51 g, 40.0mmol) was added portion-wise. After addition, the resulting mixture wasstirred at room temperature for another 5 h, then quenched with water(40 mL), stirred for 1 h and filtered. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(MeOH/DCM (v/v)=1/25) to give the product as a light yellow solid (1.20g, yield 22.4%).

LC-MS (ESI, pos. ion) m/z: 269.3 [M+H]⁺.

Step 4) tert-butyl9-((2,5-dichloropyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate

To a solution of 2,4,5-trichloropyrimidine (495.9 mg, 2.7 mmol) inethanol (20 mL) were added tert-butyl9-amino-3-azaspiro[5.5]undecane-3-carboxylate (1.08 g, 4.0 mmol) andEt₃N (413.6 mg, 4.1 mmol). The mixture was stirred at room temperaturefor 12 h and then concentrated in vacuo. The residue was purified bysilica gel column chromatography (EtOAc/PE (v/v)=1/10 to 1/7) to givethe product as a light yellow solid (387.1 mg, yield 34.5%).

LC-MS (ESI, pos. ion) m/z: 415.0 [M+H]⁺.

Step 5) tert-butyl9-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate

To a solution of tert-butyl9-((2,5-dichloropyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate(230.0 mg, 0.55 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride(185.4 mg, 1.39 mmol) in n-BuOH (3 mL) was added DIPEA (215.7 mg, 1.67mmol). The mixture was stirred at 150° C. overnight and thenconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/100 to 1/70) to give the title productas a light yellow solid (87.0 mg, yield 33.0%).

LC-MS (ESI, pos. ion) m/z: 476.1 [M+H]⁺.

Step 6)5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine

To a solution of tert-butyl9-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate(87.0 mg, 0.18 mmol) in dichloromethane (5 mL) was added a solution ofHCl in EtOAc (2 mL, 8 mmol). The mixture was stirred at room temperaturefor 5 h and then concentrated in vacuo. The residue was dissolved inMeOH (2 mL) and adjusted to pH=10 with a saturated Na₂CO₃ aqueoussolution, then extracted with DCM (20 mL×3). The combined organic phaseswere washed with brine (20 mL), dried over anhydrous Na₂SO₄, thenfiltered and concentrated in vacuo. The residue was purified bypreparative TLC (MeOH/DCM (v/v)=1/5) to give the title product as alight yellow solid (54.0 mg, yield 78.6%).

LC-MS (ESI, pos. ion) m/z: 376.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.73 (s, 1H), 7.85 (s, 1H), 7.72 (s,1H), 7.44 (s, 1H), 6.62 (s, 1H), 3.77 (s, 3H), 3.03 (m, 5H), 1.84-1.23(m, 12H).

Step 7)1-(9-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecan-3-yl)-2-cyclopropylethanone

To a solution of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine(60.2 mg, 0.16 mmol), 2-cyclopropylacetic acid (24.7 mg, 0.25 mmol) andtriethylamine (34.5 mg, 0.34 mmol) in dichloromethane (5 mL) were addedEDCI (61.4 mg, 0.32 mmol) and HOAT (44.2 mg, 0.33 mmol), the reactionmixture was stirred at room temperature for 3 h. The reaction wasquenched with H₂O (15 mL) and extracted with DCM (3×10 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/30) to afford the target product as awhite solid (47.5 mg, yield 64.8%).

LC-MS (ESI, pos. ion) m/z: 458.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.86 (s, 1H), 7.69-7.62 (m, 1H),7.54-7.47 (m, 1H), 6.63 (s, 1H), 5.12 (s, 1H), 4.00-3.91 (m, 1H), 3.87(s, 3H), 3.64-3.54 (m, 2H), 3.46-3.33 (m, 2H), 2.28 (d, J=6.6 Hz, 2H),2.02-1.94 (m, 2H), 1.82-1.70 (m, 2H), 1.60-1.55 (m, 2H), 1.43-1.27 (m,6H), 1.09-1.01 (m, 1H), 0.61-0.52 (m, 2H), 0.21-0.12 (m, 2H).

Example 211-(9-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecan-3-yl)-2-methylpropan-2-ol

To a solution of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine(100.3 mg, 0.27 mmol) in N,N-dimethylformamide (2 mL) was added2,2-dimethyloxirane (58.5 mg, 0.81 mmol), the reaction mixture wasstirred in a sealed tube at 80° C. overnight. The reaction was quenchedwith H₂O (20 mL) and extracted with DCM (3×10 mL). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by silica gel column chromatography(MeOH/DCM (v/v)=1/80 to 1/50) to afford the target product as a lightyellow solid (69.4 mg, yield 58.1%).

LC-MS (ESI, pos. ion) m/z: 448.5 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.85 (s, 1H), 7.68 (s, 1H), 7.48 (s,1H), 6.60 (s, 1H), 5.11 (d, J=7.1 Hz, 1H), 3.95-3.90 (m, 1H), 3.87 (s,3H), 3.57-3.46 (m, 1H), 3.37-3.29 (m, 1H), 2.67-2.52 (m, 2H), 2.31 (s,2H), 1.99-1.90 (m, 2H), 1.78-1.71 (m, 2H), 1.50-1.35 (m, 6H), 1.29-1.26(m, 2H), 1.15 (s, 6H).

Example 22(9-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecan-3-yl)(cyclopropyl)methanone

To a solution of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine(150 mg, 0.3990 mmol) and cyclopropanecarbonyl chloride (51 mg, 0.48785mmol) in dichloromethane (10 mL) was added N,N-diethylethanamine (61 mg,0.60283 mmol). The reaction mixture was stirred at rt overnight andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=50/1 to 25/1) to give the title productas a white solid (105 mg, yield 59.26%).

LC-MS (ESI, pos. ion) m/z: 444.3 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.01 (s, 1H), 7.85 (s, 1H), 7.73 (s,1H), 7.44 (s, 1H), 6.66 (d, J=7.8 Hz, 1H), 3.94 (s, 1H), 3.77 (s, 3H),3.63 (s, 2H), 3.45 (s, 2H), 1.97 (s, 2H), 1.78 (d, J=13.2 Hz, 2H), 1.68(d, J=15.1 Hz, 2H), 1.61 (d, J=13.4 Hz, 3H), 1.47 (s, 1H), 1.36 (s, 1H),1.22-1.13 (m, 2H), 0.69 (dd, J=9.8, 5.8 Hz, 4H).

Example 235-chloro-N⁴-(3-(cyclopropylsulfonyl)-3-azaspiro[5.5]undecan-9-yl)-N²-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

To a solution of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine(150 mg, 0.3990 mmol) and cyclopropanesulfonyl chloride (67.5 mg, 0.480mmol) in dichloromethane (10 mL) was added TEA (61 mg, 0.60283 mmol).The mixture was stirred at rt overnight and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=50/1 to 25/1) to give the title product as a white solid (150 mg,yield 78.31%).

LC-MS (ESI, pos. ion) m/z: 480.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.86 (s, 1H), 7.65 (s, 1H), 7.51 (s,1H), 6.68 (s, 1H), 5.11 (d, J=7.4 Hz, 1H), 3.94 (dd, J=7.3, 3.6 Hz, 1H),3.87 (s, 3H), 3.29 (dd, J=11.0, 5.2 Hz, 4H), 2.27 (ddd, J=12.9, 8.1, 4.9Hz, 1H), 2.02-1.93 (m, 2H), 1.77 (d, J=13.2 Hz, 2H), 1.72-1.67 (m, 2H),1.56-1.50 (m, 2H), 1.43 (t, J=12.1 Hz, 2H), 1.37-1.32 (m, 2H), 1.18 (dd,J=4.8, 2.0 Hz, 2H), 0.98 (dd, J=7.7, 2.1 Hz, 2H).

Example 245-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-ethylhexahydrocyclopenta[c]pyrrole-2(1H)-sulfonamide

To a suspension of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(0.20 g, 0.60 mmol) in anhydrous DCM (5.0 mL) were added Et₃N (0.25 mL,1.80 mmol) and N-ethylsulfamoyl chloride (0.18 g, 1.24 mmol) and thereaction mixture was stirred at room temperature overnight. The reactionwas quenched by addition of water (10 mL), extracted with DCM (50 mL×3).The combined organic layers were dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/(a solution of NH₃ in MeOH) (3M) (v/v)=100/1 to50/1) to afford the title compound as a white solid (0.12 g, yield 45%).

LC-MS (ESI, pos. ion) m/z: 441.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.86 (s, 1H), 7.64 (s, 1H), 7.51 (s,1H), 6.62 (s, 1H), 5.38 (d, J=7.5 Hz, 1H), 4.39-4.26 (m, 1H), 4.16 (t,J=5.9 Hz, 1H), 3.87 (s, 3H), 3.25-3.17 (m, 6H), 2.81-2.69 (m, 2H),2.52-2.41 (m, 2H), 1.49-1.38 (m, 2H), 1.22 (t, J=7.2 Hz, 3H).

Example 25 phenyl5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a suspension of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(0.10 g, 0.30 mmol) in DCM (8 mL) were added triethylamine (0.047 g,0.47 mmol) and phenyl carbonochloridate (0.059 g, 0.38 mmol). Thereaction mixture was stirred at room temperature for 2 h, then quenchedby the addition of water (20 mL), extracted with DCM (50 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/(a solution of NH₃ in MeOH) (3M) (v/v)=100/1 to 50/1to 30/1) to afford the title compound as a yellow solid (85 mg, yield62%).

LC-MS (ESI, pos. ion) m/z: 454.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.87 (s, 1H), 7.64 (s, 1H), 7.52 (s,1H), 7.35 (t, J=7.9 Hz, 2H), 7.19 (t, J=7.4 Hz, 1H), 7.13 (d, J=7.6 Hz,2H), 6.69 (s, 1H), 5.31 (d, J=7.3 Hz, 1H), 4.50-4.36 (m, 1H), 3.87 (s,3H), 3.78-3.64 (m, 2H), 3.64-3.49 (m, 2H), 2.86-2.73 (m, 2H), 2.59-2.46(m, 2H), 1.54-1.45 (m, 2H).

Example 261-(5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-2-phenylethanone

To a suspension of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(51 mg, 0.15 mmol) in DCM (5 mL) were added triethylamine (0.026 g, 0.26mmol) and 2-phenylacetyl chloride (0.033 g, 0.21 mmol). The reactionmixture was stirred at room temperature overnight, then quenched byaddition of water (10 mL), extracted with DCM (30 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica chromatography(DCM/3M NH₃ in MeOH (v/v)=100/1 to 50/1 to 30/1) to afford the crudeproduct as a yellow solid. The solid was purified further by preparativeTLC (DCM/(a solution of NH₃ in MeOH (3M)) (v/v)=40/1) to afford thetitle compound as a yellow solid (28 mg, yield 41%).

LC-MS (ESI, pos. ion) m/z: 452.5 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.86 (s, 1H), 7.63 (s, 1H), 7.51 (s,1H), 7.37-7.27 (m, 4H), 6.62 (s, 1H), 5.12 (d, J=6.7 Hz, 1H), 4.39-4.27(m, 1H), 3.86 (s, 3H), 3.73-3.64 (m, 3H), 3.61-3.50 (m, 2H), 3.46-3.38(m, 1H), 2.75-2.61 (m, 2H), 2.53-2.31 (m, 2H), 1.36-1.29 (m, 2H).

Example 27(5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(phenyl)methanone

To a suspension of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(0.058 g, 0.17 mmol) in DCM (3 mL) was added triethylamine (0.023 g,0.23 mmol). The reaction mixture was cooled down to 0° C., then addedbenzoyl chloride (0.027 g, 0.19 mmol). The mixture was stirred at 0° C.for 30 min and then quenched by addition of water (20 mL), extractedwith DCM (30 mL×3). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/(a solution of NH₃ inMeOH) (3M) (v/v)=100/1 to 50/1 to 30/1) to afford the crude product as ayellow solid. The solid was purified further by preparative TLC (DCM/3MNH₃ in MeOH (v/v)=40/1) to afford the title compound as a yellow solid(32 mg, yield 42%).

LC-MS (ESI, pos. ion) m/z: 438.4 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.87 (s, 1H), 7.66 (s, 1H), 7.54 (s,1H), 7.52-7.48 (m, 2H), 7.43-7.38 (m, 3H), 6.80 (s, 1H), 5.26 (d, J=6.8Hz, 1H), 4.39-4.27 (m, 1H), 3.99-3.89 (m, 1H), 3.86 (s, 3H), 3.78-3.69(m, 1H), 3.67-3.58 (m, 1H), 3.46-3.35 (m, 1H), 2.80-2.65 (m, 2H),2.58-2.47 (m, 1H), 2.41-2.29 (m, 1H), 1.58-1.47 (m, 2H).

Example 285-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

Step 1) Phenyl Phenylcarbamate

To a solution of aniline (941.3 mg, 10.11 mmol) and Et₃N (2.07 g, 20.46mmol) in DCM (20 mL) was added phenyl carbonochloridate (3.80 g, 24.27mmol) at 0° C. After addition, the reaction mixture was stirred at 0° C.for 0.5 h and then moved to rt for another 2 h. The reaction wasquenched with water (30 mL), and extracted with DCM (100 mL×3). Thecombined organic phases were washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (EtOAc/PE (v/v)=1/20) togive the title compound as a white solid (2.16 g, 100%).

LC-MS (ESI, pos. ion) m/z: 214.2 [M+H]⁺.

Step 2)5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

To a solution of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(164.9 mg, 0.49 mmol) and Et₃N (224.6 mg, 2.22 mmol) in EtOH (20 mL) wasadded phenyl phenylcarbamate (202.1 mg, 0.95 mmol). The reaction mixturewas stirred at rt overnight, then quenched with water (30 mL), andextracted with DCM (100 mL×3). The combined organic phases were washedwith brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=20/1) to give the title compound as abeige solid (165.2 mg, yield 73.8%).

LC-MS (ESI, pos. ion) m/z: 453.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.88 (s, 1H), 7.67 (s, 1H), 7.56 (s,1H), 7.42 (d, J=7.7 Hz, 2H), 7.32 (d, J=7.5 Hz, 2H), 7.06 (t, J=7.4 Hz,1H), 6.74 (s, 1H), 6.22 (s, 1H), 5.38 (d, J=7.3 Hz, 1H), 448 (m, 1H),3.90 (s, 3H), 3.80 (m, 2H), 3.52 (dd, J=10.6, 2.2 Hz, 2H), 2.85 (m, 2H),2.52 (dt, J=14.6, 7.5 Hz, 2H), 1.56 (m, 2H).

Example 29(5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(morpholino)methanone

Step 1) 4-nitrophenyl morpholine-4-carboxylate

To a solution of 4-nitrophenyl carbonochloridate (389.3 mg, 1.93 mmol)and Et₃N (304.3 mg, 3.01 mmol) in DCM (10 mL) was added morpholine(185.0 mg, 2.12 mmol). The reaction mixture was stirred at rt for 3.5 h,then quenched with water (30 mL), and extracted with DCM (100 mL×3). Thecombined organic phases were washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) togive the title compound as a yellow green solid (487.2 mg, yield 100%).

LC-MS (ESI, pos. ion) m/z: 253.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.28 (d, J=9.1 Hz, 2H), 7.33 (d, J=9.1Hz, 2H), 3.79 (m, 4H), 3.71 (s, 2H), 3.61 (s, 2H).

Step 2)(5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(morpholino)methanone

To a solution of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(85.7 mg, 0.26 mmol) and Et₃N (276.2 mg, 2.73 mmol) in EtOH (10 mL) wasadded 4-nitrophenyl morpholine-4-carboxylate (82.4 mg, 0.33 mmol). Thereaction mixture was stirred at 100° C. in a sealed tube overnight, thencooled down to rt, and quenched with water (30 mL), then extracted withDCM (100 mL×3). The combined organic phases were washed with brine (100mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/40) to give the title compound as a beige solid (72.7 mg, yield63.4%).

LC-MS (ESI, pos. ion) m/z: 447.4 [M+H]⁺;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 7.86 (s, 1H), 7.68 (s, 1H), 7.56 (s,1H), 7.29 (s, 1H), 5.38 (d, J=4.6 Hz, 1H), 4.30 (s, 1H), 3.88 (s, 3H),3.71 (m, 6H), 3.47 (m, 4H), 2.66 (s, 2H), 2.41 (s, 2H), 2.32 (s, 2H),1.51 (s, 2H); ¹³C NMR (150 MHz, CDCl₃) δ (ppm): 163.0, 157.9, 157.6,152.8, 131.0, 123.4, 120.9, 104.1, 72.4, 66.7, 61.7, 54.0, 53.5, 46.9,40.8, 39.4, 38.7.

Example 306-(5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyridazine-3-carbonitrile

To a solution of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(85.8 mg, 0.26 mmol) and Et₃N (80.4 mg, 0.80 mmol) in EtOH (10 mL) wasadded 6-chloropyridazine-3-carbonitrile (72.8 mg, 0.52 mmol). Thereaction mixture was stirred at rt overnight, quenched with water (30mL), and extracted with DCM (100 mL×3). The combined organic phases werewashed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/50) to give the title compound as abeige solid (109.6 mg, yield 97.6%).

LC-MS (ESI, pos. ion) m/z: 437.4 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.03 (s, 1H), 7.85 (m, 2H), 7.75 (s,1H), 7.45 (s, 1H), 7.02 (d, J=9.6 Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 4.59(m, 1H), 3.79 (s, 3H), 3.72 (m, 4H), 2.84 (s, 2H), 2.33 (m, 2H), 1.62(m, 2H);

¹³C NMR (150 MHz, CDCl₃) δ (ppm): 158.2, 157.5, 131.1, 130.1, 128.2,124.2, 118.2, 111.8, 72.7, 60.7, 52.9, 40.8, 39.1, 37.6.

Example 31N⁴-(2-(tert-butylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)-5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

Step 1)N⁴-(2-(tert-butylsulfinyl)octahydrocyclopenta[c]pyrrol-5-yl)-5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

To a solution of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(98.5 mg, 0.30 mmol) and Et₃N (132.8 mg, 1.31 mmol) in DCM (8 mL) wasadded a solution of 2-methylpropane-2-sulfinic chloride (92.8 mg, 0.66mmol) in DCM (2 mL) at 0° C. The reaction mixture was stirred at 0° C.for 1 h, then quenched with water (50 mL), and the resulting mixture wasextracted with DCM (100 mL×3). The combined organic phases were washedwith brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/50) to give the title compound as apale yellow solid (129.5 mg, yield 100%).

LC-MS (ESI, pos. ion) m/z: 438.2 [M+H]⁺;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 7.86 (s, 1H), 7.69 (s, 1H), 7.52 (s,1H), 6.98 (s, 1H), 5.50 (d, J=5.0 Hz, 1H), 4.29 (m, 1H), 3.89 (s, 3H),3.49 (dd, J=11.5, 6.9 Hz, 1H), 3.41 (dd, J=11.0, 2.9 Hz, 1H), 3.17 (m,2H), 2.66 (m, 2H), 2.38 (m, 2H), 1.59 (m, 2H), 1.22 (s, 9H).

Step 2)N⁴-(2-(tert-butylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)-5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

To a solution ofN⁴-(2-(tert-butylsulfinyl)octahydrocyclopenta[c]pyrrol-5-yl)-5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine(133.6 mg, 0.30 mmol) in DCM (10 mL) was added mCPBA (138.6 mg, 0.68mmol) portionwise. The reaction mixture was stirred at reflux overnightand mCPBA (131.5 mg, 0.65 mmol) was added portionwise again. Thereaction mixture was continued to stir at reflux overnight. The mixturewas cooled down to rt, and adjusted to pH=10 with a saturated Na₂CO₃aqueous solution, then extracted with DCM (100 mL×3). The combinedorganic phases were washed with brine (100 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (MeOH/DCM (v/v)=1/80) to give the titlecompound as a beige solid (42.7 mg, yield 30.8%).

LC-MS (ESI, pos. ion) m/z: 454.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 454.1795 [M+H]⁺, calculated value forC₁₉H₂₉ClN₇O₂S [M+H]⁺ is 454.1792;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.87 (s, 1H), 7.66 (s, 1H), 7.53 (s,1H), 7.02 (s, 1H), 5.29 (d, J=7.0 Hz, 1H), 4.26 (m, 1H), 3.88 (s, 3H),3.55 (d, J=10.8 Hz, 2H), 3.39 (dd, J=10.5, 6.0 Hz, 2H), 2.69 (d, J=4.5Hz, 2H), 2.44 (m, 2H), 1.50 (m, 2H), 1.41 (s, 9H);

¹³C NMR (150 MHz, CDCl₃) δ (ppm): 169.0, 158.0, 157.7, 152.9, 131.0,123.3, 120.9, 64.8, 60.8, 55.2, 52.9, 41.3, 39.2, 38.1, 30.6, 24.5,19.1.

Example 322-(5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)octahydrocyclopenta[c]pyrrol-5-yl)acetonitrile

Step 1) tert-butyl5-(cyanomethylene)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a suspension of NaH (60% [w/w] mineral oil suspension, 5.65 g, 141.25mmol) in THF (200 mL) at 0° C. was dropwise addeddiethyl(cyanomethyl)phosphonate (25.98 g, 146.66 mmol). After addition,the reaction mixture was stirred at 0° C. for 1 h and then moved to rtfor another 2 h. A solution of tert-butyl5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (15.34 g, 68.09mmol) in THF (100 mL) was dropwise added to the above mixture. Thereaction mixture was stirred at rt overnight, then quenched with water(150 mL), and extracted with EtOAc (250 mL×3). The combined organicphases were washed with brine (250 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (EtOAc/PE (v/v)=1/10) to give the titlecompound as orange oil (12.94 g, yield 76.5%).

LC-MS (ESI, pos. ion) m/z: 193.2 [M−C₄H₈+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 5.29 (s, 1H), 3.58 (s, 2H), 3.39 (s,1H), 3.13 (m, 3H), 2.82 (m, 2H), 2.59 (d, J=18.3 Hz, 1H), 2.44 (d,J=14.3 Hz, 1H), 1.48 (s, 9H).

Step 2) tert-butyl5-amino-5-(cyanomethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a solution of tert-butyl5-(cyanomethylene)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (14.69g, 59.16 mmol) in MeOH (30 mL) was added concentrated ammonia (28% [w/w]in water, 163.03 g, 1.30 mol). The reaction was stirred in a autoclaveat 110° C. for 64 h, then cooled down to rt and concentrated in vacuo.The residue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/60) to give the title compound as yellow oil (6.28 g, yield40%).

LC-MS (ESI, pos. ion) m/z: 266.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 3.50 (s, 2H), 3.46 (m, 2H), 3.28 (d,J=8.7 Hz, 2H), 2.96 (m, 2H), 2.58 (s, 2H), 1.97 (dd, J=13.2, 8.0 Hz,2H), 1.55 (m, 2H), 1.47 (s, 9H).

Step 3) tert-butyl5-(cyanomethyl)-5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a solution of 2,4,5-trichloropyrimidine (3.65 g, 19.90 mmol) andtert-butyl5-amino-5-(cyanomethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(5.23 g, 19.71 mmol) in n-BuOH (80 mL) was added Et₃N (4.13 g, 40.81mmol). After addition, the reaction mixture was stirred in a sealed tubeat 150° C. overnight, then cooled down to rt and concentrated in vacuo.The residue was purified by silica gel column chromatography (EtOAc/PE(v/v)=1/4) to give the title compound as yellow oil (1.11 g, yield13.5%).

LC-MS (ESI, pos. ion) m/z: 412.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.13 and 8.12 (s, 1H), 5.82 and 5.40(s, 1H), 3.50 (m, 2H), 3.38 (s, 2H), 3.30 and 3.19 (s, 2H), 2.85 (m,2H), 2.72 (m, 2H), 1.92 and 1.73 (dd, J=13.6, 6.1 Hz, 2H), 1.49 and 1.47(s, 9H).

Step 4) tert-butyl5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-5-(cyanomethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a suspension of tert-butyl5-(cyanomethyl)-5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (631.5 mg, 1.53 mmol)and 1-methyl-1H-pyrazol-4-amine hydrochloride (213.2 mg, 1.60 mmol) inn-BuOH (10 mL) was added Et₃N (322.1 mg, 3.18 mmol). The reactionmixture was stirred at 150° C. in a sealed tube overnight andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/50) to give the title compound as ayellow solid (283.0 mg, yield 39.1%).

LC-MS (ESI, pos. ion) m/z: 473.3 [M+H]⁺.

Step 5)2-(5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)octahydrocyclopenta[c]pyrrol-5-yl)acetonitrile

To a solution of tert-butyl5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-5-(cyanomethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(272.0 mg, 0.58 mmol) in DCM (10 mL) was added a solution of HCl inEtOAc (10 mL, 40 mmol). The reaction mixture was stirred at rt for 0.5 hand concentrated in vacuo. The residue was dissolved in water (10 mL)and the resulting mixture was adjusted to pH=10 with a saturated Na₂CO₃aqueous solution, then extracted with DCM (100 mL×3). The combinedorganic phases were washed with brine (100 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the titlecompound as a beige solid (109.9 mg, yield 51.2%).

LC-MS (ESI, pos. ion) m/z: 373.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 373.1658 [M+H]⁺, calculated value forC₁₇H₂₂ClN₈ [M+H]⁺ is 373.1656;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.91 (s, 1H), 7.64 (s, 1H), 7.44 (s,1H), 6.57 (s, 1H), 6.43 (s, 1H), 3.90 (s, 3H), 3.24 (s, 2H), 2.86 (m,2H), 2.78 (d, J=10.2 Hz, 2H), 2.69 (d, J=2.6 Hz, 2H), 2.49 (dd, J=13.3,7.7 Hz, 2H), 1.79 (dd, J=13.4, 5.2 Hz, 2H);

¹³C NMR (150 MHz, CDCl₃) δ (ppm): 158.0, 157.6, 153.6, 122.7, 122.4,118.1, 105.4, 63.1, 53.5, 44.4, 41.6, 39.3, 29.7, 25.0.

Example 331-(9-((5-chloro-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecan-3-yl)ethanone

Step 1) tert-butyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate

To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (10.0 g,46.9 mmol) and KOH (1.3 g, 23.5 mmol) in EtOH (200 mL) was addedbut-3-en-2-one (3.9 g, 56.3 mmol), the mixture was stirred at 70° C. for16 h and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (EtOAc/PE (v/v)=1/4) to give the product as brownoil (5.2 g, yield 41.8%).

MS (ESI, pos. ion) m/z: 210.2 [M−55]⁺.

Step 2) tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate

To a solution of tert-butyl9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (5.2 g, 19.6 mmol) in DCM(80 mL) was added Pd/C (0.5 g, mass %=10%) and the suspension wasstirred under a H₂ atmosphere at room temperature overnight. Thereaction mixture was filtered and concentrated in vacuo, then theresidue was purified by silica gel column chromatography (EtOAc/PE(v/v)=1/4) to give the title compound as brown oil (3.1 g, yield 59.0%).

MS (ESI, pos. ion) m/z: 212.1 [M−55]⁺.

Step 3) tert-butyl 9-amino-3-azaspiro[5.5]undecane-3-carboxylate

To a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate(5.35 g, 20.0 mmol) in EtOH (40 mL) were added a solution of NH₃ in MeOH(7M, 40 mL, 280.0 mmol) and Ti(Oi-Pr)₄ (11.30 g, 40.0 mmol), the mixturewas stirred at room temperature overnight. And then NaBH₄ (1.51 g, 40.0mmol) was added portionwise. After addition, the resulting mixture wasstirred at room temperature for another 5 h, then quenched with water(40 mL), stirred for 1 h and filtered. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(MeOH/DCM (v/v)=1/25) to give the product as a light yellow solid (1.20g, yield 22.4%).

MS (ESI, pos. ion) m/z: 269.3 [M+H]⁺.

Step 4) tert-butyl9-((2,5-dichloropyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate

To a solution of 2,4,5-trichloropyrimidine (495.9 mg, 2.7 mmol) inethanol (20 mL) were added tert-butyl9-amino-3-azaspiro[5.5]undecane-3-carboxylate (1.08 g, 4.0 mmol) andEt₃N (413.6 mg, 4.1 mmol). The mixture was stirred at room temperaturefor 12 h and then concentrated in vacuo. The residue was purified bysilica gel column chromatography (EtOAc/PE (v/v)=1/10 to 1/7) to givethe product as a light yellow solid (387.1 mg, yield 34.5%).

MS (ESI, pos. ion) m/z: 415.0 [M+H]⁺.

Step 5) N-(2,5-dichloropyrimidin-4-yl)-3-azaspiro[5.5]undecan-9-amine

To a solution of tert-butyl3-[(2,5-dichloropyrimidin-4-yl)amino]-9-azaspiro[5.5]undecane-9-carboxylate(1.05 g, 2.53 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc(25 mL, 3 mmol, 2 M). The reaction mixture was stirred at rt for 1 h.The reaction solution was directly washed with water (50 mL×2). Thecombined aqueous phases were adjusted to pH=12 with NaOH aqueoussolution (4 M) and then extracted with the mixture solvent of DCM andMeOH (10/1 (v/v), 100 mL×5). The combined organic layers were dried withNa₂SO₄, filtered and concentrated in vacuo to give the title compound asa white solid (708 mg, yield 89%).

MS (ESI, pos. ion) m/z: 315.2 [M+H]⁺.

Step 6)1-(9-((2,5-dichloropyrimidin-4-yl)amino)-3-azaspiro[5.5]undecan-3-yl)ethanone

To a solution ofN-(2,5-dichloropyrimidin-4-yl)-3-azaspiro[5.5]undecan-9-amine (301.8 mg,0.9575 mmol) and TEA (202.6 mg, 2.002 mmol) in DCM (20 mL) was addedacetyl acetate (120.4 mg, 1.179 mmol). The reaction mixture was stirredat rt for 30 min and concentrate in vacuo. The residue was purified bysilica gel column chromatography (DCM/MeOH (v/v)=70/1) to give the titlecompound as a white solid (190 mg, yield 55.54%).

MS (ESI, pos. ion) m/z: 357.3 [M+H]⁺.

Step 7) tert-butyl4-(4-((4-((3-acetyl-3-azaspiro[5.5]undecan-9-yl)amino)-5-chloropyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a solution of1-(9-((2,5-dichloropyrimidin-4-yl)amino)-3-azaspiro[5.5]undecan-3-yl)ethanone(312.4 mg, 0.8743 mmol), tert-butyl4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (337.8 mg, 1.268mmol) and cesium carbonate (817.4 mg, 2.509 mmol) in 1,4-dioxane (14 mL)were added BINAP (54.1 mg, 0.0869 mmol) and Pd(OAc)₂ (20.3 mg, 0.0904mmol). The reaction mixture was heated to 100° C. and stirred for 6 hand then concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=40/1) to give the title compoundas a yellow solid (280 mg, yield 54.5%).

MS (ESI, pos. ion) m/z: 587.6 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.85 (s, 1H), 7.70 (s, 1H), 7.53 (s,1H), 6.92 (s, 1H), 5.13 (d, J=7.1 Hz, 1H), 4.31-4.13 (m, 3H), 3.99-3.88(m, 1H), 3.72-3.66 (m, 2H), 3.56 (dd, J=11.4, 6.1 Hz, 2H), 3.40 (dd,J=11.4, 6.3 Hz, 2H), 2.87 (t, J=11.6 Hz, 2H), 2.15-2.09 (m, 2H), 2.08(s, 3H), 2.01-1.91 (m, 4H), 1.89-1.86 (m, 2H), 1.80-1.70 (m, 3H),1.62-1.53 (m, 3H), 1.46 (s, 9H).

Step 8)1-(9-((5-chloro-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecan-3-yl)ethanone

tert-butyl4-(4-((4-((3-acetyl-3-azaspiro[5.5]undecan-9-yl)amino)-5-chloropyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(280 mg, 0.4768 mmol) was added to a solution of HCl in EtOAc (8 mL, 16mmol, 2 M). The reaction mixture was stirred for 2 h at rt, thenconcentrated directly in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/(a solution of NH₃ in MeOH (7 M) (v/v)=20/1)to give the title compound as a yellow solid (57.2 mg, yield 24.6%).

MS (ESI, pos. ion) m/z: 487.4 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 487.2672 [M+H]⁺, calculated value forC₂₄H3₆ClN₈O [M+H]⁺ is 487.2701;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.84 (s, 1H), 7.74 (s, 1H), 7.57 (d,J=6.6 Hz, 1H), 7.18-6.96 (m, 1H), 5.13 (d, J=4.9 Hz, 1H), 4.31-4.21 (m,1H), 3.98-3.87 (m, 1H), 3.58-3.51 (m, 2H), 3.45-3.36 (m, 4H), 2.96 (t,J=11.8 Hz, 2H), 2.28-2.21 (m, 2H), 2.19-2.11 (m, 2H), 2.07 (d, J=1.4 Hz,3H), 2.00-1.89 (m, 2H), 1.77-1.67 (m, 2H), 1.58-1.50 (m, 2H), 1.47-1.29(m, 6H);

¹³C NMR (100 MHz, CDCl₃) δ (ppm): 169.0, 158.0, 157.4, 153.0, 130.7,123.4, 117.6, 104.2, 57.6, 50.7, 49.9, 44.1, 42.5, 39.4, 37.4, 34.2,31.3, 30.9, 29.7, 27.5, 21.4.

Example 345-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-cyclopropylhexahydrocyclopenta[c]pyrrole-2(1H)-sulfonamide

Step 1) cyclopropanaminium cyclopropylsulfamate

To a solution of cyclopropanamine (2.94 g, 51.5 mmol) in anhydrous DCM(50.0 mL) was slowly added a solution of sulfurochloridic acid (2.00 g,17.18 mmol) in anhydrous DCM (9.0 mL) over 30 min at 0° C. The reactionmixture was stirred at 0° C. for another 30 min, then move to roomtemperature and stirred for another 1 h, then filtered. The filtratecake was washed with anhydrous DCM (10.0 mL) and dried in vacuo to givethe title compound as a white solid (3.33 g, yield 100%).

MS (ESI, pos. ion) m/z: 58.2 [M₁]⁺;

MS (ESI, neg. ion) m/z: 136.0 [M₂]⁻.

Step 2) Cyclopropylsulfamoyl Chloride

To a suspension of cyclopropanaminium cyclopropylsulfamate (3.33 g, 17.1mmol) in anhydrous toluene (50.0 mL) was added phosphorus pentachloride(3.57 g, 17.1 mmol). The mixture was heated to 75° C. and stirred for 2h and then cooled down to room temperature and filtered. The filtratecake was washed with anhydrous toluene (10.0 mL). The filtrate wasconcentrated in vacuo to afford the title compound as brown liquid (0.65g, yield 24%).

Step 3)5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-cyclopropylhexahydrocyclopenta[c]pyrrole-2(1H)-sulfonamide

To a suspension of5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)-N⁴-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine(0.10 g, 0.30 mmol) and TEA (0.21 mL, 1.50 mmol) in anhydrous DCM (10.0mL) was added cyclopropylsulfamoyl chloride (0.10 g, 0.63 mmol) at 0° C.The mixture was stirred at 0° C. for 15 min and then move to roomtemperature and stirred overnight. The resulting mixture wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/(a solution of NH₃ in MeOH (3 M) (v/v)=100/1 to50/1) to get the title compound as a white solid (30 mg, yield 22%).

MS (ESI, pos. ion) m/z: 453.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 453.1585 [M+H]⁺, calculated value forC₁₈H2₆ClN₈O₂S [M+H]⁺ is 453.1582;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 7.86 (s, 1H), 7.64 (s, 1H), 7.49 (s,1H), 6.62 (s, 1H), 5.33 (d, J=7.3 Hz, 1H), 4.72 (d, J=4.5 Hz, 1H),4.38-4.27 (m, 1H), 3.88 (s, 3H), 3.32-3.25 (m, 4H), 2.78-2.72 (m, 2H),2.62-2.57 (m, 1H), 2.51-2.45 (m, 2H), 1.48-1.41 (m, 2H), 0.73-0.65 (m,4H);

¹³C NMR (150 MHz, CDCl₃) δ (ppm): 158.03, 157.65, 153.02, 131.05,123.19, 121.01, 104.35, 54.24, 52.70, 40.51, 39.27, 24.82, 18.45, 6.90.

Example 351-(9-((5-chloro-2-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecan-3-yl)ethanone

To a solution of1-(9-((2,5-dichloropyrimidin-4-yl)amino)-3-azaspiro[5.5]undecan-3-yl)ethanone(83 mg, 0.534 mmol) and 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol(129 mg, 0.361 mmol) in 1,4-dioxane (20 mL) were added cesium carbonate(225 mg, 0.690 mmol), Pd(OAc)₂ (15 mg, 0.067 mmol) and BINAP (45 mg,0.072 mmol). The reaction mixture was stirred at 100° C. overnight andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM=1/30) to give the title compound as a yellowsolid (30 mg, yield 17.5%).

MS (ESI, pos. ion) m/z: 476.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 476.2540 [M+H]⁺, calculated value forC₂₃H₃₅ClN₇O₂ [M+H]⁺ is 476.2463;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.85 (s, 1H), 7.75 (d, J=11.3 Hz, 1H),7.57 (d, J=12.3 Hz, 1H), 7.00 (s, 1H), 5.16 (s, 1H), 4.02-3.90 (m, 2H),3.93 (d, J=16.2 Hz, 1H), 3.60-3.52 (m, 2H), 3.42-3.99 (m, 2H), 2.09 (s,3H), 1.99-1.94 (m, 2H), 1.76-1.72 (s, 2H), 1.59-1.53 (m 2H), 1.48-1.33(m, 6H), 1.18 (s, 6H);

¹³C NMR (100 MHz, CDCl₃) δ (ppm): 169.11, 157.86, 157.50, 152.72,131.52, 130.04, 123.10, 121.78, 70.92, 62.25, 42.59, 37.48, 34.38,30.97, 29.82, 27.67, 27.03, 26.92, 21.62.

Example 365-((5-chloro-2-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-cyclopropylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

Step 1) tert-butyl5-((5-chloro-2-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a suspension of tert-butyl5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (143.5 mg, 0.38 mmol) and1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol (68.8 mg, 0.44 mmol) in1,4-dioxane (20 mL) were added Pd(OAc)₂ (19.3 mg, 0.09 mmol), BINAP(98%, 54.4 mg, 0.08 mmol) and cesium carbonate (98%, 272.3 mg, 0.82mmol). The reaction mixture was stirred at 100° C. overnight andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (EtOAc/PE (v/v)=2/1) to give the title compound as ayellow solid (56.2 mg, yield 29.7%).

MS (ESI, pos. ion) m/z: 492.4 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.85 (s, 1H), 7.75 (s, 1H), 7.64 (s,1H), 5.36 (d, J=5.8 Hz, 1H), 4.41 (m, 1H), 4.03 (s, 2H), 3.50 (m, 2H),3.38 (d, J=9.5 Hz, 2H), 2.71 (m, 2H), 2.46 (m, 2H), 1.46 (m, 11H), 1.20(s, 6H).

Step 2)1-(4-((5-chloro-4-((octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

To a solution of tert-butyl5-((5-chloro-2-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(176.4 mg, 0.45 mmol) in DCM (10 mL) was added a solution of HCl inEtOAc (10 mL, 40 mmol, 4M). The reaction mixture was stirred at rt for0.5 h and then concentrated in vacuo. The residue was dissolved in water(10 mL) and adjusted to pH=10 with a saturated Na₂CO₃ aqueous solution,then extracted with DCM (100 mL×3). The combined organic phases werewashed with brine (100 mL), dried over anhydrous Na₂SO₄, thenconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/8) to give the title compound as a paleyellow solid (64.5 mg, yield 45.9%).

MS (ESI, pos. ion) m/z: 392.0 [M+H]⁺;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 7.82 (s, 2H), 7.79 (s, 1H), 7.58 (s,1H), 6.64 (s, 1H), 4.52 (m, 1H), 4.03 (s, 2H), 3.51 (s, 1H), 2.90 (m,4H), 2.71 (s, 2H), 2.26 (m, 2H), 1.51 (d, J=13.4 Hz, 2H), 1.20 (s, 6H).

Step 3)5-((5-chloro-2-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-cyclopropylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

To a solution of1-(4-((5-chloro-4-((octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-methylpropan-2-ol(55.9 mg, 0.14 mmol) and Et₃N (110.1 mg, 1.09 mmol) in EtOH (10 mL) wasadded phenyl cyclopropylcarbamate (45.2 mg, 0.26 mmol). The reactionmixture was stirred at 50° C. overnight, cooled down to rt, and quenchedwith water (30 mL), then extracted with DCM (100 mL×3). The combinedorganic phases were washed with brine (100 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the titlecompound as a beige solid (52.6 mg, yield 77.6%).

MS (ESI, pos. ion) m/z: 475.2[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 475.2339 [M+H]⁺, calculated value forC₂₂H3₂ClN₈O₂[M+H]⁺ is 475.2337;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 7.86 (s, 1H), 7.76 (s, 1H), 7.62 (s,1H), 7.20 (s, 1H), 5.42 (s, 1H), 4.56 (s, 1H), 4.42 (s, 1H), 4.03 (s,2H), 3.47 (2, 2H), 3.34 (s, 2H), 2.75 (s, 2H), 2.66 (s, 1H), 2.43 (s,2H), 1.49 (s, 2H), 1.20 (s, 6H), 0.73 (s, 2H), 0.49 (s, 2H);

¹³C NMR (150 MHz, CDCl₃) δ (ppm): 158.2, 157.8, 157.6, 152.6, 131.6,122.9, 121.9, 70.8, 62.1, 53.2, 52.2, 41.1, 39.1, 29.7, 26.9, 23.3, 6.9.

Example 371-(4-((5-chloro-4-((3-(methylsulfonyl)-3-azaspiro[5.5]undecan-9-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

Step 1)N-(2,5-dichloropyrimidin-4-yl)-3-(methylsulfonyl)-3-azaspiro[5.5]undecan-9-amine

To a solution ofN-(2,5-dichloropyrimidin-4-yl)-3-azaspiro[5.5]undecan-9-amine (220 mg,0.698 mmol) in DCM (10 mL) were added TEA (109 mg, 1.07 mmol) and DMAP(19.1 mg, 0.223 mmol). The reaction mixture was cooled to 0° C. andmethanesulfonyl chloride (102 mg, 0.890 mmol) was added. The resultingmixture was stirred at 0° C. overnight and then concentrated in vacuo.The residue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/80) to give the title compound as a yellow solid (176 mg, yield64.1%).

MS (ESI, pos. ion) m/z: 393.0 [M+H]⁺.

Step 2)1-(4-((5-chloro-4-((3-(methylsulfonyl)-3-azaspiro[5.5]undecan-9-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

To a solution ofN-(2,5-dichloropyrimidin-4-yl)-3-(methylsulfonyl)-3-azaspiro[5.5]undecan-9-amine(142 mg, 0.361 mmol) and 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol(70 mg, 0.451 mmol) in 1,4-dioxane (20 mL) were added cesium carbonate(234 mg, 0.718 mmol), Pd(OAc)₂ (16 mg, 0.071 mmol) and BINAP (45 mg,0.072 mmol). The mixture was stirred at 105° C. overnight andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/MeOH=40/1) to give the title compound as a yellowsolid (80 mg, yield 43.3%).

MS (ESI, pos. ion) m/z: 512.0 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 512.2209 [M+H]⁺, calculated value forC₂₂H₃₅N₇O₃S [M+H]⁺ is 512.2131;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.96 (s, 2H), 8.02 (s, 1H), 7.86 (s,1H), 7.73 (s, 1H), 7.50 (s, 1H), 3.96 (s, 2H), 3.12-3.10 (m, 4H), 2.86(s, 3H), 2.00-1.98 (m, 1H), 1.77-1.64 (m, 10H), 1.44-1.42 (m, 2H), 1.06(s, 6H).

Example 381-(4-((5-chloro-4-((2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propan-2-ol

Step 1)-(4-nitro-1H-pyrazol-1-yl)propan-2-ol

To a solution of 4-nitro-1H-pyrazole (1.02 g, 9.02 mmol) and1-bromopropan-2-ol (3.65 g, 26.3 mmol) in DMF (10 mL) was added cesiumcarbonate (8.65 g, 26.5 mmol). The mixture was stirred at 100° C. for3.5 h. The reaction was quenched with water (50 mL) and extracted withEtOAc (100 mL×3). The combined organic phases were dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the title compound asyellow oil (1.51 g, yield 97.8%).

MS (ESI, pos. ion) m/z: 172.2 [M+H]⁺.

Step 2) 1-(4-amino-1H-pyrazol-1-yl)propan-2-ol

To a solution of 1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol (1.51 g, 8.82mmol) in EtOH (20 mL) was added Pd/C (300 mg, mass %=10%). The mixturewas stirred at rt in a high pressure autoclave under 2 MPa H₂ atmosphereovernight and filtered. The filtrate was concentrated in vacuo and theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=1/30) to give the title compound as a brown solid (1.0 g, yield80.3%). MS (ESI, pos. ion) m/z: 142.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.17 (s, 1H), 7.03 (s, 1H), 4.16-4.10(m, 1H), 4.02 (dd, J=13.8, 2.7 Hz, 1H), 3.85 (dd, J=13.8, 7.9 Hz, 1H),2.95 (s, 2H), 1.19 (d, J=6.3 Hz, 3H).

Step 3)N-(2,5-dichloropyrimidin-4-yl)-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-amine

To a solution ofN-(2,5-dichloropyrimidin-4-yl)octahydrocyclopenta[c]pyrrol-5-amine (500mg, 1.83 mmol) in DCM (10 mL) were added triethylamine (340 mg, 3.36mmol) and DMAP (45 mg, 0.368 mmol). The mixture was cooled to 0° C. andmethanesulfonyl chloride (310 mg, 2.71 mmol) was added. The mixture wasstirred at 0° C. overnight and concentrated in vacuo. The residue waspurified by silica gel column chromatography (MeOH/DCM (v/v)=1/100) togive the title compound as a yellow solid (300 mg, yield 46.7%).

MS (ESI, pos. ion) m/z: 351.2 [M+H]⁺.

Step 4)1-(4-((5-chloro-4-((2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propan-2-ol

To a solution ofN-(2,5-dichloropyrimidin-4-yl)-2-(methylsulfonyl)octahydro-cyclopenta[c]pyrrol-5-amine(132 mg, 0.375 mmol) and 1-(4-amino-1H-pyrazol-1-yl)propan-2-ol (82 mg,0.580 mmol) in 1,4-dioxane (20 mL) were added cesium carbonate (241 mg,0.739 mmol), Pd(OAc)₂ (16 mg, 0.071 mmol) and BINAP (46 mg, 0.073 mmol).The reaction mixture was stirred at 105° C. overnight and concentratedin vacuo. The residue was purified by silica gel column chromatography(MeOH/DCM (v/v)=1/30) to give the title compound as a yellow solid (100mg, yield 58.4%).

MS (ESI, pos. ion) m/z: 456.4 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 456.1580 [M+H]⁺, calculated value forC₁₈H₂₇ClN₇O₃S [M+H]⁺ is 456.1506;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.04 (s, 1H), 7.85 (d, J=8.1 Hz, 1H),7.82 (s, 1H), 7.42 (s, 1H), 6.97 (d, J=7.4 Hz, 1H), 4.91 (s, 1H),4.43-4.37 (m, 1H), 3.96-3.89 (m, 3H), 3.23 (dd, J=9.3, 7.1 Hz, 2H),3.13-3.10 (m, 2H), 2.91 (s, 3H), 2.69 (s, 2H), 2.25 (s, 2H), 1.52 (dd,J=18.4, 10.1 Hz, 2H), 1.01 (d, J=5.8 Hz, 3H);

¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 157.65, 157.37, 153.29, 129.43,123.35, 119.87, 65.70, 58.91, 53.59, 40.06, 39.99, 37.56, 32.85, 20.90.

Example 391-(4-((5-chloro-4-((2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

To a solution ofN-(2,5-dichloropyrimidin-4-yl)-2-(methylsulfonyl)octahydro-cyclopenta[c]pyrrol-5-amine(160 mg, 0.455 mmol) and 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol(110 mg, 0.708 mmol) in 1,4-dioxane (20 mL) were added cesium carbonate(310 mg, 0.951 mmol), Pd(OAc)₂ (21 mg, 0.093 mmol) and BINAP (57 mg,0.091 mmol). The reaction mixture was stirred at 105° C. overnight andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/30) to give the title compound as ayellow solid (100 mg, yield 46.7%).

MS (ESI, pos. ion) m/z: 470.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 470.1773 [M+H]⁺, calculated value forC₁₉H₂₉ClN₇O₃S [M+H]⁺ is 470.1663;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.04 (s, 1H), 7.85 (d, J=5.8 Hz, 2H),7.42 (s, 1H), 6.96 (d, J=7.7 Hz, 1H), 4.44-4.37 (m, 1H), 3.93 (s, 2H),3.23 (dd, J=9.3, 7.0 Hz, 2H), 3.17 (d, J=5.2 Hz, 1H), 3.13-3.10 (m, 2H),2.91 (s, 3H), 2.69 (s, 2H), 2.25 (s, 2H), 1.51 (dd, J=18.9, 11.7 Hz,2H), 1.04 (s, 6H);

¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 157.69, 157.39, 153.34, 129.25,123.35, 120.32, 69.42, 62.42, 53.62, 48.63, 40.02, 37.61, 32.86, 27.22.

Example 405-((5-chloro-2-((1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-cyclopropylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

Step 1) tert-butyl 3-hydroxypyrrolidine-1-carboxylate

To a suspension of pyrrolidin-3-ol hydrochloride (2.00 g, 16.2 mmol) andtriethylamine (6.80 mL, 48.8 mmol) in anhydrous DCM (40.0 mL) was added(Boc)₂O (4.24 g, 19.4 mmol). The mixture was stirred at room temperaturefor 3 h, then concentrated in vacuo. The residue was purified by silicagel column chromatography (EtOAc/PE (v/v)=1/4 to 1/2 to 1/1) to affordthe title compound as colorless sticky liquid (2.20 g, 76%). MS (ESI,pos. ion) m/z: 132.2 [(M−56)+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 4.48-4.33 (m, 1H), 3.51-3.24 (m, 4H),1.97-1.82 (m, 2H), 1.44 (s, 9H).

Step 2) tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

To a suspension of 4-nitro-1H-pyrazole (0.50 g, 4.43 mmol) in THF (35.0mL) were added tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.00 g,5.33 mmol) and triphenylphosphane (1.75 g, 6.68 mmol), and the mixturewas cooled down to 0° C. To the above mixture was added a solution ofDIAD (1.36 g, 6.73 mmol) in anhydrous THF (15.0 mL) over 20 min. Afteraddition, the resulting mixture was stirred at 0° C. for 30 min, andthen move to room temperature and stirred overnight. The mixture wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (EtOAc/PE (v/v)=10/1 to 5/1) to afford the crude titlecompound as brown sticky liquid (2.10 g, containing impurity, the targetproduct was just for 1.25 g, yield 100%).

MS (ESI, pos. ion) m/z: 227.0 [(M−56)+H]⁺.

Step 3) tert-butyl 3-(4-amino-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

To a suspension of tert-butyl3-(4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (1.25 g, 4.43 mmol)in EtOH (30.0 mL) was added Pd/C (mass %=10%, 0.30 g). The mixture wasstirred at room temperature overnight under hydrogen atmosphere. Thenthe mixture was filtered and the filter cake was washed with MeOH (10.0mL). The filtrate was concentrated in vacuo, and the residue waspurified by silica chromatography (DCM 100% to DCM/(a solution of NH₃ inMeOH (3M)) (v/v)=100/1 to 50/1) to afford the title compound as brownsticky liquid (0.65 g, yield 58%).

MS (ESI, pos. ion) m/z: 253.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.16 (s, 1H), 7.01 (s, 1H), 4.79-4.67(m, 1H), 3.82-3.73 (m, 1H), 3.70-3.44 (m, 3H), 2.90 (s, 2H), 2.36-2.24(m, 2H), 1.45 (s, 9H).

Step 4)N-cyclopropyl-5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

To a solution ofN-(2,5-dichloropyrimidin-4-yl)octahydrocyclopenta[c]pyrrol-5-amine(110.5 mg, 0.41 mmol) in ethanol (2 mL) was added phenylN-cyclopropylcarbamate (144.2 mg, 0.81 mmol). The reaction mixture wasstirred at 50° C. for 10 h and then concentrated in vacuo. The residuewas purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1)to afford the title compound as brown oil (138.2 mg, yield 96%). MS(ESI, pos. ion) m/z: 356.0 [M+H]⁺.

Step 5) tert-butyl3-(4-((5-chloro-4-((2-(cyclopropylcarbamoyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

To a solution ofN-cyclopropyl-5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide(152.2 mg, 0.43 mmol) and tert-butyl3-(4-aminopyrazol-1-yl)pyrrolidine-1-carboxylate (130.4 mg, 0.52 mmol)in 1,4-dioxane (4 mL) were added Pd(OAc)₂ (10.2 mg, 0.05 mmol), BINAP(27.3 mg, 0.04 mmol) and cesium carbonate (275.6 mg, 0.85 mmol). Thereaction mixture was stirred at 100° C. for 6 h under N₂ atmosphere andthen concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=60/1 to 30/1) to afford the titlecompound as a brown solid (124.3 mg, yield 51%).

MS (ESI, pos. ion) m/z: 572.3 [M+H]⁺.

Step 6)5-((5-chloro-2-((1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-cyclopropylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

A solution of HCl in EtOAc (8 mL, 24 mmol, 3M) was added to a solutionof tert-butyl3-(4-((5-chloro-4-((2-(cyclopropylcarbamoyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate(124.2 mg, 0.22 mmol) in DCM (2 mL). The resulting mixture was stirredat room temperature for 1 h and then concentrated in vacuo. The residuewas diluted with water (4 mL), and the resulting mixture was adjusted topH=9 with 1M NaOH aqueous solution and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=20/1 to DCM/(a solution of NH₃ in MeOH (7M)) (v/v)=10/1) to affordthe target compound as a red solid (45.4 mg, yield 44%).

MS (ESI, pos. ion) m/z: 236.6 [(M+2H)/2]⁺;

HRMS (ESI, pos. ion) m/z: 472.2303 [M+H]⁺, calculated value forC₂₂H₃₁ClN₉O [M+H]⁺ is 472.2335;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 7.86 (s, 1H), 7.78 (s, 1H), 7.54 (s,1H), 6.78 (s, 1H), 5.35 (d, J=7.5 Hz, 1H), 4.79 (ddd, J=10.9, 7.2, 3.5Hz, 1H), 4.52 (s, 1H), 4.41 (dd, J=15.3, 7.7 Hz, 1H), 3.47 (dd, J=10.1,7.6 Hz, 2H), 3.35-3.31 (m, 3H), 3.27 (dd, J=12.1, 6.4 Hz, 1H), 3.12-3.06(m, 1H), 2.73 (t, J=10.7 Hz, 2H), 2.65 (dd, J=5.3, 3.4 Hz, 1H),2.47-2.40 (m, 2H), 2.38-2.31 (m, 1H), 2.28-2.18 (m, 3H), 1.53-1.45 (m,2H), 0.76-0.68 (m, 2H), 0.50-0.44 (m, 2H);

¹³C NMR (150 MHz, CDCl₃) δ (ppm): 158.2, 157.9, 157.5, 153.0, 131.1,129.9, 123.3, 119.0, 61.9, 53.6, 53.2, 52.2, 46.3, 41.2, 39.1, 33.0,23.4, 6.9.

Example 415-((5-chloro-2-((1-(2-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-cyclopropylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamideand Example 42N-cyclopropyl-5-((2-((1-(2-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

To a suspension of N-cyclopropyl-5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide (535.5 mg, 1.50 mmol)and 1-(4-amino-1H-pyrazol-1-yl)propan-2-ol (271.2 mg, 1.92 mmol) in1,4-dioxane (30 mL) were added Pd(OAc)₂ (73.0 mg, 0.32 mmol), BINAP(98%, 194.8 mg, 0.31 mmol) and cesium carbonate (98%, 1.04 g, 3.13mmol). The reaction mixture was stirred at 100° C. overnight andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=20/1) to give5-((5-chloro-2-((1-(2-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-cyclopropylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamideas a light pink solid (279.8 mg, yield 40.4%) and used another elutionsystem (DCM/MeOH (v/v)=10/1) to giveN-cyclopropyl-5-((2-((1-(2-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide as a light pink solid(134.2 mg, yield 20.9%).

Characterization Data of Example 415-((5-chloro-2-((1-(2-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-cyclopropylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

MS (ESI, pos. ion) m/z: 461.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 461.2150 [M+H]⁺, calculated value forC₂₁H₃₀ClN₈O₂[M+H]⁺ is 461.2180;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 7.86 (s, 1H), 7.76 (s, 1H), 7.59 (s,1H), 6.82 (s, 1H), 5.37 (d, J=7.4 Hz, 1H), 4.54 (s, 1H), 4.42 (m, 1H),4.22 (m, 1H), 4.13 (dd, J=13.8, 2.7 Hz, 1H), 3.96 (dd, J=13.8, 8.0 Hz,1H), 3.57 (s, 1H), 3.48 (dd, J=9.9, 7.3 Hz, 2H), 3.34 (d, J=10.0 Hz,2H), 2.76 (m, 2H), 2.67 (m, 1H), 2.45 (m, 2H), 1.51 (m, 2H), 1.25 (d,J=6.3 Hz, 3H), 0.74 (m, 2H), 0.50 (m, 2H);

¹³C NMR (150 MHz, CDCl₃) δ (ppm): 158.2, 158.0, 157.5, 153.0, 131.6,123.0, 121.4, 67.2, 58.9, 53.2, 52.2, 41.1, 39.1, 23.3, 20.1, 6.9.

Characterization Data of Example 42N-cyclopropyl-5-((2-((1-(2-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

MS (ESI, pos. ion) m/z: 427.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 427.2542 [M+H]⁺, calculated value forC₂₁H₃₁N₈O₂ [M+H]⁺ is 427.2570;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 7.90 (d, J=4.7 Hz, 1H), 7.83 (s, 1H),7.53 (s, 1H), 6.70 (s, 1H), 5.78 (d, J=5.8 Hz, 1H), 4.97 (s, 1H), 4.52(s, 1H), 4.22 (m, 2H), 4.14 (dd, J=13.8, 2.4 Hz, 1H), 3.96 (dd, J=13.8,8.1 Hz, 1H), 3.77 (s, 1H), 3.48 (dd, J=10.1, 7.6 Hz, 2H), 3.31 (d,J=10.4 Hz, 2H), 2.75 (m, 2H), 2.65 (m, 1H), 2.42 (m, 2H), 1.44 (m, 2H),1.25 (d, J=6.3 Hz, 3H), 0.74 (m, 2H), 0.49 (m, 2H);

¹³C NMR (150 MHz, CDCl₃) δ (ppm): 162.6, 159.8, 158.1, 132.0, 124.8,122.8, 122.1, 67.2, 59.0, 52.0, 50.8, 41.2, 39.2, 23.3, 20.1, 6.9.

Example 435-((5-chloro-2-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-cyclopropylhexahydrocyclopenta[c]pyrrole-2(1H)-sulfonamide

Step 1)N-cyclopropyl-5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-sulfonamide

To a suspension ofN-(2,5-dichloropyrimidin-4-yl)octahydrocyclopenta[c]pyrrol-5-amine (0.27g, 0.987 mmol 7) and TEA (0.70 mL, 5.00 mmol) in anhydrous DCM (10.0 mL)was slowly added a solution of cyclopropylsulfamoyl chloride (0.31 g,1.98 mmol) in anhydrous DCM (5.0 mL) at 0° C. After addition, themixture was move to room temperature and stirred for another 30 min. Thereaction was quenched by addition of water (20 mL) and allowed tostratification. The organic layer was separated and the aqueous layerwas extracted with DCM (30 mL×3). The combined organic layer was washedwith brine (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (EtOAc/PE (v/v)=1/3) to afford the title compound as ayellow solid (0.17 g, yield 44%).

MS (ESI, pos. ion) m/z: 392.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.02 (s, 1H), 5.70 (d, J=7.7 Hz, 1H),4.51-4.38 (m, 1H), 3.85 (s, 1H), 3.35-3.22 (m, 4H), 2.84-2.71 (m, 2H),2.63-2.57 (m, 1H), 2.53-2.44 (m, 2H), 1.50-1.37 (m, 2H), 0.75-0.70 (m,4H).

Step 2)5-((5-chloro-2-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-cyclopropylhexahydrocyclopenta[c]pyrrole-2(1H)-sulfonamide

To a suspension ofN-cyclopropyl-5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-sulfonamide(0.11 g, 0.28 mmol) in anhydrous 1,4-dioxane (10.0 mL) was added1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol (54 mg, 0.35 mmol),Pd(OAc)₂ (14 mg, 0.06 mmol), BINAP (37 mg, 0.06 mmol) and cesiumcarbonate (0.20 g, 0.61 mmol). The mixture was degassed for 2 min andrefilled with N₂ and heated to 105° C. and stirred for 3 h. The mixturewas concentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=50/1 to 30/1) to get the crude product.The crude product was purified once again by preparative TLC (DCM/MeOH(v/v)=20/1) to afford the title compound as a brown solid (55 mg, yield38%).

MS (ESI, pos. ion) m/z: 511.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 511.1974 [M+H]⁺, calculated value forC₂₁H3₂ClN₈O₃S [M+H]⁺ is 511.2001;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.06 (s, 1H), 7.87 (s, 1H), 7.84 (s,1H), 7.54 (d, J=1.9 Hz, 1H), 7.43 (s, 1H), 6.97 (s, 1H), 4.67 (s, 1H),4.44-4.32 (m, 1H), 3.94 (s, 2H), 3.25-3.21 (m, 2H), 3.11-3.03 (m, 2H),2.75-2.65 (m, 2H), 2.46-2.44 (m, 1H), 2.30-2.20 (m, 2H), 1.56-1.46 (m,2H), 1.05 (s, 6H), 0.63-0.56 (m, 2H), 0.56-0.49 (m, 2H).

Example 441-(4-((5-chloro-4-((2-(cyclopropylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propan-2-ol

Step 1)2-(cyclopropylsulfonyl)-N-(2,5-dichloropyrimidin-4-yl)octahydrocyclopenta[c]pyrrol-5-amine

To a solution of triethylamine (120 mg, 1.17402 mmol) andN-(2,5-dichloropyrimidin-4-yl)octahydrocyclopenta[c]pyrrol-5-amine (100mg, 0.3661 mmol) in DCM (20 mL, 311 mmol) was dropwise addedcyclopropanesulfonyl chloride (77 mg, 0.5477 mmol) at 0° C. After theaddition, the reaction mixture was stirred at rt for 6 h andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=40/1) to give the title compound as alight yellow solid (102 mg, yield 73.9%).

MS (ESI, pos. ion) m/z: 377.3 [M+H]⁺.

Step 2)1-(4-((5-chloro-4-((2-(cyclopropylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propan-2-ol

To a solution of 2-(cyclopropylsulfonyl)-N-(2,5-dichloropyrimidin-4-yl)octahydrocyclopenta[c]pyrrol-5-amine (101.2 mg, 0.2682 mmol),1-(4-aminopyrazol-1-yl)propan-2-ol (58.8 mg, 0.417 mmol), BINAP (15.2mg, 0.0237 mmol and Pd(OAc)₂ (6.3 mg, 0.028 mmol) in 1,4-dioxane (15 mL)was added cesium carbonate (261.0 mg, 0.800 mmol). The reaction wasstirred at 100° C. under N₂ atmosphere overnight and then concentratedin vacuo. The residue was purified by silica gel column chromatography(DCM/MeOH (v/v)=40/1) to give the crude compound as a light yellowsolid. The crude product was then purified by preparative TLC (DCM/MeOH(v/v)=30/1) to give the title compound as a white solid (30 mg, yield23.2%).

MS (ESI, pos. ion) m/z: 482.1 [M+H];

¹H NMR (600 MHz, CDCl₃) δ (ppm): 7.86 (s, 1H), 7.73 (s, 1H), 7.57 (s,1H), 6.63 (s, 1H), 5.38 (d, J=7.4 Hz, 1H), 4.33 (m, 1H), 4.21 (m, 1H),4.11 (dd, J=13.8, 2.5 Hz, 1H), 3.94 (dd, J=13.8, 8.0 Hz, 1H), 3.36 (m,2H), 3.31 (m, 2H), 2.77 (m, 2H), 2.47 (m, 2H), 2.35 (m, 1H), 1.49 (m,2H), 1.23 (d, J=6.3 Hz, 3H), 1.21 (m, 2H), 1.01 (m, 2H);

¹³C NMR (150 MHz, CDCl₃) δ (ppm): 157.9, 157.6, 152.9, 131.5, 129.9,123.0, 121.2, 67.3, 58.8, 54.2, 52.5, 40.5, 39.3, 29.7, 25.1, 20.1, 4.5.

Example 455-((5-chloro-2-((1-(2-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-ethylhexahydrocyclopenta[c]pyrrole-2(1H)-sulfonamide

Step 1)5-((2,5-dichloropyrimidin-4-yl)amino)-N-ethylhexahydrocyclopenta[c]pyrrole-2(1H)-sulfonamide

To a solution ofN-(2,5-dichloropyrimidin-4-yl)octahydrocyclopenta[c]pyrrol-5-amine(303.4 mg, 1.111 mmol) in DCM (5 mL) was added TEA (354.7 mg, 3.505mmol). The mixture was cooled to 0° C., then the solution ofN-ethylsulfamoyl chloride (100 mg, 0.6964 mmol) in DCM (4 mL) was added.The reaction mixture was warmed to rt and stirred overnight, thenconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=70/1) to give the title compound as awhite solid (95 mg, yield 22.49%).

MS (ESI, pos. ion) m/z: 380.4 [M+H]⁺.

Step 2)5-((5-chloro-2-((1-(2-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-ethylhexahydrocyclopenta[c]pyrrole-2(1H)-sulfonamide

To a mixture of5-((2,5-dichloropyrimidin-4-yl)amino)-N-ethylhexahydrocyclopenta[c]pyrrole-2(1H)-sulfonamide(95 mg, 0.2498 mmol) and 1-(4-aminopyrazol-1-yl) propan-2-ol (44.6 mg,0.316 mmol) were added Cs₂CO₃ (168.4 mg, 0.5168 mmol), BINAP (17.2 mg,0.0276 mmol), Pd(OAc)₂ (6.8 mg, 0.030 mmol) and 1,4-dioxane (10 mL). Thereaction mixture was heated to reflux and stirred for 4 h under N₂atmosphere and concentrated in vacuo. The residue was purified by silicagel column chromatography (DCM/MeOH (v/v)=20/1) to give the titlecompound as a light yellow solid (35.4 mg, yield 29.2%).

MS (ESI, pos. ion) m/z: 485.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 485.1853 [M+H]⁺, calculated value forC₁₉H₃₀ClN₈O₃S [M+H]⁺ is 485.1850;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 7.84 (s, 1H), 7.72 (s, 1H), 7.57 (s,1H), 6.96-6.78 (m, 1H), 5.44 (d, J=6.9 Hz, 1H), 4.35-4.29 (m, 1H), 4.27(t, J=5.7 Hz, 1H), 4.23-4.16 (m, 1H), 4.11 (dd, J=13.8, 2.4 Hz, 1H),3.94 (dd, J=13.8, 8.0 Hz, 1H), 3.27-3.15 (m, 6H), 2.79-2.72 (m, 2H),2.51-2.40 (m, 2H), 1.49-1.40 (m, 2H), 1.22 (t, J=7.1 Hz, 6H);

¹³C NMR (150 MHz, CDCl₃) δ (ppm): 157.9, 157.7, 152.7, 131.6, 122.9,121.4, 67.2, 58.9, 54.4, 52.7, 40.4, 39.5, 39.1, 20.1, 15.7.

Example 461-(4-((5-chloro-4-((2-((cyclopropylmethyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propan-2-ol

Step 1) Sodium Cyclopropylmethanesulfonate

To a saturated Na₂SO₃ aqueous solution (10 mL) was added1-bromo-1-methylcyclopropane (1.00 g, 7.4074 mmol). After the addition,the reaction mixture was stirred at 100° C. overnight and thenconcentrated in vacuo. The residue was suspended in EtOH (20 mL) and thesuspension system was stirred at 50° C. for 5 h. Filtered and collectedthe filter cake to give the title compound as a white solid (1.12 g,yield 95.6%).

Step 2) Cyclopropylmethanesulfonyl Chloride

To a solution of sodium cyclopropylmethanesulfonate (1.12 g, 7.08 mmol)in THF (10 mL, 123 mmol) was dropwise added thionyl chloride (2.1 mL, 29mmol). After the addition, the reaction was stirred at 100° C. for 5 hand concentrated in vacuo to give the product as brown oil (1.00 g,yield 91.3%).

Step 3)2-((cyclopropylmethyl)sulfonyl)-N-(2,5-dichloropyrimidin-4-yl)octahydro-cyclopenta[c]pyrrol-5-amine

To a solution ofN-(2,5-dichloropyrimidin-4-yl)octahydrocyclopenta[c]pyrrol-5-amine(200.2 mg, 0.7329 mmol) and triethylamine (120 mg, 1.1740 mmol) in DCM(30 mL, 467 mmol) was dropwise added a solution ofcyclopropylmethanesulfonyl chloride (200 mg, 1.2935 mmol) in DCM (5 mL)at 0° C. After the addition, the reaction was stirred at rt for 5 h andthen concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=50/1) to give the target compoundas a light yellow solid (180.1 mg, yield 62.8%).

MS (ESI, pos. ion) m/z: 391.2 [M+H]⁺.

Step 4)1-(4-((5-chloro-4-((2-((cyclopropylmethyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propan-2-ol

To a solution of2-((cyclopropylmethyl)sulfonyl)-N-(2,5-dichloropyrimidin-4-yl)octahydro-cyclopenta[c]pyrrol-5-amine (180.5 mg, 0.46 mmol),1-(4-aminopyrazol-1-yl)propan-2-ol (97.3 mg, 0.69 mmol), BINAP (29.3 mg,0.046 mmol) and Pd(OAc)₂ (10.2 mg, 0.044 mmol) in 1,4-dioxane (15 mL),was added cesium carbonate (451.2 mg, 1.38 mmol). The reaction wasstirred at 100° C. under N₂ atmosphere overnight and then concentratedin vacuo. The residue was purified by silica gel column chromatography(DCM/MeOH (v/v)=40/1) to give the crude compound as a light yellowsolid. The crude product was then purified by preparative TLC (DCM/MeOH(v/v)=30/1) to give the title compound as a light yellow solid (125.6mg, yield 55%).

MS (ESI, pos. ion) m/z: 496.1 [M+H];

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.05 (s, 1H), 7.84 (d, J=13.4 Hz,2H), 7.43 (s, 1H), 6.98 (d, J=5.3 Hz, 1H), 4.98 (s, 1H), 4.39 (d, J=4.9Hz, 1H), 3.93 (s, 3H), 3.34 (s, 2H), 3.16 (d, J=8.7 Hz, 2H), 3.05 (d,J=6.3 Hz, 2H), 2.68 (s, 2H), 2.24 (s, 2H), 1.51 (s, 2H), 1.23 (s, 1H),1.01 (s, 3H), 0.60 (d, J=6.0 Hz, 2H), 0.35 (s, 2H);

¹³C NMR (100 MHz, DMSO-d₆) δ (ppm): 158.1, 157.8, 153.8, 130.0, 123.8,120.4, 110.0, 66.1, 59.3, 53.6, 52.8, 37.8, 21.3, 5.3, 4.8.

Example 475-((5-chloro-2-((1-(2-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-cyclopropylhexahydrocyclopenta[c]pyrrole-2(1H)-sulfonamide

Step 1)N-cyclopropyl-5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-sulfonamide

To a solution ofN-(2,5-dichloropyrimidin-4-yl)octahydrocyclo-penta[c]pyrrol-5-amine (200mg, 0.7322 mmol) and TEA (225 mg, 2.2013 mmol) in DCM (40 mL, 622 mmol)was dropwise added a solution of N-cyclopropylsulfamoyl chloride (228mg, 1.4653 mmol) in DCM (4 mL, 62 mmol) at 0° C. After the addition, thereaction was stirred at rt for 6 h and then concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=40/1) to give the compound as a light yellow solid (120 mg, yield41.8%).

MS (ESI, pos. ion) m/z: 392.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.98 (s, 1H), 5.81 (d, J=7.6 Hz, 1H),5.08 (s, 1H), 4.41 (m, 1H), 3.24 (d, J=2.6 Hz, 4H), 2.75 (s, 2H), 2.55(s, 1H), 2.45 (m, 2H), 1.43 (m, 2H), 0.68 (m, 2H), 0.64 (m, 2H).

Step 2)5-((5-chloro-2-((1-(2-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-cyclopropylhexahydrocyclopenta[c]pyrrole-2(1H)-sulfonamide

To a solution of Pd(OAc)₂ (10 mg, 0.0436512 mmol), BINAP (26 mg, 0.04mmol), 1-(4-aminopyrazol-1-yl)propan-2-ol (113 mg, 0.80 mmol),N-cyclopropyl-5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-sulfonamide(158 mg, 0.4028 mmol) in 1,4-dioxane (25 mL) was added cesium carbonate(400 mg, 1.23 mmol). The reaction mixture was stirred at 100° C. underN₂ atmosphere overnight and then concentrated in vacuo. The residue waspurified by silica gel column chromatography (MeOH/DCM (v/v)=1/40) togive the crude compound as a light yellow solid. The crude product wasthen purified by preparative TLC (MeOH/DCM (v/v)=1/30) to give the titlecompound as a white solid (48 mg, yield 24.0%).

MS (ESI, pos. ion) m/z: 497.2 [M+H]⁺;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 9.02 (s, 1H), 7.84 (s, 1H), 7.79 (s,1H), 7.51 (s, 1H), 7.41 (s, 1H), 6.94 (d, J=6.3 Hz, 1H), 4.36 (m, 1H),3.91 (s, 3H), 3.20 (m, 2H), 3.15 (d, J=5.1 Hz, 1H), 3.05 (d, J=9.0 Hz,2H), 2.67 (s, 2H), 2.43 (m, 1H), 2.24 (s, 2H), 1.49 (m, 2H), 0.99 (d,J=5.2 Hz, 3H), 0.57 (m, 2H), 0.51 (m, 2H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 158.1, 157.8, 153.8, 130.1, 129.9,123.8, 120.3, 66.8, 66.2, 59.4, 54.0, 49.1, 38.1, 24.9, 21.3, 6.6.

Example 482-(2-acetyl-5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)octahydrocyclopenta[c]pyrrol-5-yl)acetonitrile

To a mixture of2-(5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)octahydrocyclopenta[c]pyrrol-5-yl)acetonitrile(92.8 mg, 0.25 mmol) and Et₃N (60.4 mg, 0.60 mmol) in DCM (10 mL) wereadded a solution of acetyl acetate (40.8 mg, 0.40 mmol) in DCM (2 mL).The reaction mixture was stirred at rt for 15 min, quenched with H₂O (30mL) and extracted with DCM (100 mL×3). The combined organic phases werewashed with brine (100 mL), dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM (v/v)=1/20) to give the title compound as abeige solid (85.9 mg, yield 83.2%).

MS (ESI, pos. ion) m/z: 415.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 415.1763 [M+H]⁺, calculated value forC₁₉H₂₄ClN₈O [M+H]⁺ is 415.1762;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94 (s, 1H), 7.64 (s, 1H), 7.47 (d,J=9.1 Hz, 1H), 6.86 (s, 1H), 5.45 and 5.14 (s, 1H), 3.90 and 3.89 (s,3H), 3.66 and 3.38 (m, 2H), 3.63 and 3.61 (s, 2H), 3.57 and 3.12 (d,J=5.6 Hz, 2H), 2.92 (m, 2H), 2.74 (m, 1H), 2.48 (m, 1H), 2.08 and 2.05(s, 3H), 2.00 and 1.71 (m, 2H);

¹³C NMR (150 MHz, CDCl₃) δ (ppm): 169.6, 157.0 (s), 156.89, 153.8,122.4, 117.6, 117.5, 64.6, 63.3, 53.0, 52.6, 51.4, 50.4, 44.2, 43.2,43.1, 42.1, 42.0, 40.5, 40.2, 39.4, 39.3, 29.7, 25.8, 22.5.

Example 49

The compound 49 was prepared using the same synthetic methodology asdescribe in the example 32. The requisite starting materials werecommercially available, described in the literature or readilysynthesized by one skilled in the art of organic synthesis without undueexperimentation.

TABLE 2 MS (ESI, Example pos. ion) # Structure Name m/z Ex. 49

2-(5-((5-chloro-2-((1-methyl- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)octahydrocyclopenta [c]pyrrol-3a-yl)acetonitrile 373.1Biological Testing

The LC/MS/MS system used in the analysis consists of an Agilent 1200Series vacuum degasser, binary pump, well-plate autosampler,thermostatted column compartment, the Agilent G6430 Triple QuadrupoleMass Spectrometer with an electrosprayionization (ESI) source.Quantitative analysis was carried out using MRM mode. The parameters forMRM transitions are in the Table A.

TABLE A MRM 490.2→383.1 Fragmentor 230 V CE 55 V Drying Gas Temp 350° C.Nebulize 0.28 MPa Drying Gas Flow 10 L/min

An Agilent XDB-C18, 2.1×30 mm, 3.5 μM column was used for the analysis.5 μL of the samples were injected. Analysis condition: The mobile phasewas 0.1% formic acid in water (A) and 0.1% formic acid in methanol (B).The flow rate was 0.4 mL/min. And the gradient of Mobile phase was inthe Table B.

TABLE B Time Gradient of Mobile Phase B 0.5 min  5% 1.0 min 95% 2.2 min95% 2.3 min  5% 5.0 min stop

Alternatively, an Agilent 6330 series LC/MS/MS spectrometer equippedwith G1312A binary pumps, a G1367A autosampler and a G1314C UV detectorwere used in the analysis. An ESI source was used on the LC/MS/MSspectrometer. The analysis was done in positive ion mode as appropriateand the MRM transition for each analyte was optimized using standardsolution. A Capcell MP-C18 100×4.6 mm I.D., 5 μM column (Phenomenex,Torrance, Calif., USA) was used during the analysis. The mobile phasewas 5 mM ammonia acetate, 0.1% MeOH in water (A): 5 mM ammonia acetate,0.1% MeOH in acetonitrile (B) (70:30, v/v). The flow rate was 0.6mL/min. Column was maintained at ambient temperature. 20 μL of thesamples were injected.

Example A: Compound Stability in Human and Rat Liver Microsomes

Human or rat liver microsomes incubations were conducted in duplicate inpolypropylene tubes. The typical incubation mixtures consisted of humanor rat liver microsomes (0.5 mg protein/mL), compounds of interest (5μM) and NADPH (1.0 mM) in a total volume of 200 μL potassium phosphatebuffer (PBS, 100 mM, pH 7.4). Compounds were dissolved in DMSO anddiluted with PBS such that the final concentration of DMSO was 0.05%.The enzymatic reactions were commenced with the addition of proteinafter a 3-min preincubation and incubated in a water bath open to theair at 37° C. Reactions were terminated at various time points (0, 5,10, 15, 30, 60 min) by adding equal volume of ice-cold acetonitrile. Thesamples were stored at −80° C. until LC/MS/MS assays.

The concentrations of compounds in the incubation mixtures of human orrat liver microsomes were determined by a LC/MS/MS method. The ranges ofthe linearity in the concentration range were determined for each testedcompounds.

A parallel incubation was performed using denatured microsomes as thenegative control, and reactions were terminated at various time points(0, 15, 60 min) after incubation at 37° C.

Dextromethorphan (70 μM) was selected as the positive control, andreactions were terminated at various time points (0, 5, 10, 15, 30, 60min) after incubation at 37° C. Both positive and negative controlsamples were included in each assay to ensure the integrity of themicrosomal incubation system.

Data Analysis

The concentrations of compounds in human or rat liver microsomeincubations were plotted as a percentage of the relevant zero time pointcontrol for each reaction. The in vivo CL_(int) were extrapolated (ref.:Naritomi, Y.; Terashita, S.; Kimura, S.; Suzuki, A.; Kagayama, A.; andSugiyama, Y.; Prediction of human hepatic clearance from in vivo animalexperiments and in vitro metabolic studies with liver microsomes fromanimals and humans. Drug Metab. Dispos., 2001, 29: 1316-1324).

Exemplary results from selected compounds of the invention are listed inTable 3. The compounds disclosed herein exhibited desirable stabilitywhen the compounds were incubated in human and rat liver microsomes.

TABLE 3 Stability of selected compounds of the invention in human andrat liver microsomes Human Rat T_(1/2) CL_(int) T_(1/2) CL_(int) Example# (min) (mL/min/kg) (min) (mL/min/kg) Ex. 1 148.5 11.71 112.0 22.18 Ex.2 106.0 16.40 106.6 23.30 Ex. 3 554.6 3.13 3.88 639.47 Ex. 4 951.3 1.8368.73 36.14 Ex. 5 1045 1.66 NT NT Ex. 6 660.1 2.63 2641 0.94 Ex. 8 31.4555.27 16.19 153.41 Ex. 13 33.14 52.45 5.48 453.56 Ex. 14 44.17 39.363.33 745.19 Ex. 16 210.1 8.27 6.28 395.37 Ex. 17 35.74 48.64 7.15 347.32Ex. 18 145.0 11.99 9.46 262.60 Ex. 19 177.7 9.78 96.88 25.64 Ex. 21404.0 4.30 62.94 39.46 Ex. 22 65.67 26.47 3.33 745.19 Ex. 23 61.03 28.4830.03 82.71 Ex. 24 33.97 51.17 9.30 266.98 Ex. 28 24.2 72.0 3.6 689.5Ex. 29 43.20 40.24 19.77 125.63 Ex. 30 24.92 69.76 8.07 307.77 Ex. 33275.0 6.32 321.4 7.73 Ex. 34 35.73 48.65 17.80 139.53 Ex. 36 69.16 25.1330.66 81.01 Ex. 37 54.33 32.00 70.45 35.25 Ex. 38 67.14 25.89 45.4554.65 Ex. 39 49.60 35.05 39.23 63.31 Ex. 41 73.49 23.7 43.72 56.8 Ex. 42153.3 11.3 374.6 6.6 Ex. 48 310.4 5.60 100.2 24.79 NT: Not Test

Example B: Evaluation of Pharmacokinetics after Intravenous and OralAdministration of the Compounds Disclosed Herein in Mice, Rats, Dogs andMonkeys

The compounds disclosed herein are assessed in pharmacokinetic studiesin mice, rats, dogs or monkeys. The compounds are administered as awater solution, 2% HPMC+1% TWEEN80 in water solution, 5% DMSO+5% solutolin saline, 4% MC suspension or capsule. For the intravenousadministration, the animals are generally given at 0.5, 1 or 2 mg/kgdose. For the oral (p.o.) dosing, mice and rats are generally given 0.5,1, 5 or 10 mg/kg dose, and dogs and monkeys are generally given 10 mg/kgdose. The blood samples (0.3 mL) are drawn at 0.25, 0.5, 1.0, 2.0, 3.0,4.0, 6.0, 8.0, 12 and 24 h time points or 0.083, 0.25, 0.5, 1.0, 2.0,4.0, 6.0, 8.0 and 24 h time points and centrifuged at 3,000 or 4000 rpmfor 2 to 10 min. The plasma solutions are collected, and stored at −20°C. or −70° C. until analyzed by LC/MS/MS as described above.

Exemplary study results from examples disclosed herein are listed inTable 4. The compounds disclosed herein exhibited optimizedpharmacokinetic properties with good absorption and desirable oralbioavailability (F) when the compounds were administered orally orintravenously.

TABLE 4 Pharmacokinetic profiles of selected compounds of the inventionin rats iv dosing Example dose T_(1/2) AUC_(last) Cl/F Vss F # (mg/kg)(h) (ng · h/mL) (L/h/kg) (L/kg) (%) Ex. 1 1 0.64 360 2.77 1.53 61.7 Ex.8 1 0.56 558 1.86 1.55 36.9 Ex. 11 1 0.30 235 4.52 1.22 19.5 Ex. 12 10.24 278 3.61 0.99 30.5 Ex. 17 1 0.29 308 3.25 1.44 37.3 Ex. 19 1 0.35263 3.82 0.95 24.0 Ex. 20 0.5 0.70 348 1.48 1.07 91.2 Ex. 21 1 1.46 1476.54 11.9 118.2 Ex. 22 1 0.56 746 1.34 1.21 84.6 Ex. 23 1 0.62 363 2.782.07 64.4 Ex. 24 1 0.40 231 4.55 2.02 31.9 Ex. 27 1 0.22 218 4.66 0.9322.5 Ex. 28 1 0.38 168 5.95 1.99 42.0 Ex. 29 1 0.35 413 2.42 1.19 102.8Ex. 30 1 0.61 1140 0.93 0.71 268.4 Ex. 34 1 0.29 348 2.93 1.18 54.0 Ex.37 1 1.25 604 1.76 2.61 53.6 Ex. 38 1 0.42 270 3.77 1.65 35.3 Ex. 39 10.64 295 5.76 1.88 40.5 Ex. 44 1 0.86 276 3.65 1.75 31.4 Ex. 45 1 0.66267 3.74 1.97 27.1 Ex. 46 1 0.26 277 3.64 1.13 24.9 Ex. 47 1 0.71 2394.16 2.37 22.4 Ex. 48 1 0.72 485 2.08 0.81 40.7 NT: Not Test

Example C: Kinase Activity Assay

The efficacy of the compounds disclosed herein as inhibitors of proteinkinases can be evaluated as follows.

General Description for Kinase Assays

Kinase assays can be performed by measurement of incorporation of γ-³³PATP into immobilized myelin basic protein (MBP). High binding white 384well plates (Greiner) are coated with MBP (Sigma #M-1891) by incubationof 60 μL/well of 20 μg/mL MBP in Tris-buffered saline (TBS; 50 mM TrispH 8.0, 138 mM NaCl, 2.7 mM KCl) for 24 h at 4° C. Plates are washed 3×with 100 μL TBS. Kinase reactions are carried out in a total volume of34 μL in kinase buffer (according to the need to make, for example, 5 mMHepes pH 7.6, 15 mM NaCl, 0.01% bovine gamma globulin (Sigma #1-5506),10 mM MgCl₂, 1 mM DTT, 0.02% TritonX-100). Compound dilutions areperformed in DMSO and added to assay wells to a final DMSO concentrationof 1%. Each data point is measured in duplicate, and at least twoduplicate assays are performed for each individual compounddetermination. Enzyme is added to final concentrations of 10 nM or 20nM, for example. A mixture of unlabeled ATP and γ-³³P ATP is added tostart the reaction (2×10⁶ cpm of γ-³³P ATP per well (3000 Ci/mmole) and10 μM unlabeled ATP, typically. The reactions are carried out for 1 h atroom temperature with shaking. Plates are washed 7× with TBS, followedby the addition of 50 μL/well scintillation fluid (Wallac). Plates areread using a Wallac Trilux counter. This is only one format of suchassays; various other formats are possible, as known to one skilled inthe art.

The above assay procedure can be used to determine the IC₅₀ forinhibition and/or the inhibition constant, K_(i). The IC₅₀ is defined asthe concentration of compound required to reduce the enzyme activity by50% under the condition of the assay. The IC₅₀ value is estimated bypreparing a 10 point curve using a 1₂ log dilution series (for example,a typical curve may be prepared using the following compoundconcentrations: 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM,0.001 μM, 0.0003 μM and 0 μM).

Kianse General Assay Protocol

JAK1 (h)

JAK1 (h) is incubated with 20 mM Tris/HCl pH 7.5, 0.2 mM EDTA, 500 μMGEEPLYWSFPAKKK, 10 mM MgAcetate and [γ-³³P-ATP] (specific activityapprox. 500 cpm/pmol, concentration as required). The reaction isinitiated by the addition of the MgATP mix. After incubation for 40minutes at room temperature, the reaction is stopped by the addition of3% phosphoric acid solution. 10 μL of the reaction is then spotted ontoa P30 filtermat and washed three times for 5 minutes in 75 mM phosphoricacid and once in methanol prior to drying and scintillation counting.

JAK2 (h)

JAK2 (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 100 μMKTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC, 10 mM MgAcetate and [γ-³³P-ATP](specific activity approx. 500 cpm/pmol, concentration as required). Thereaction is initiated by the addition of the MgATP mix. After incubationfor 40 minutes at room temperature, the reaction is stopped by theaddition of 3% phosphoric acid solution. 10 μL of the reaction is thenspotted onto a P30 filtermat and washed three times for 5 minutes in 75mM phosphoric acid and once in methanol prior to drying andscintillation counting.

JAK3 (h)

JAK3 (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 500 μMGGEEEEYFELVKKKK, 10 mM MgAcetate and [γ-³³P-ATP] (specific activityapprox. 500 cpm/pmol, concentration as required). The reaction isinitiated by the addition of the MgATP mix. After incubation for 40minutes at room temperature, the reaction is stopped by the addition of3% phosphoric acid solution. 10 μL of the reaction is then spotted ontoa P30 filtermat and washed three times for 5 minutes in 75 mM phosphoricacid and once in methanol prior to drying and scintillation counting.

TYK2 (h)

TYK2 (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μMGGMEDIYFEFMGGKKK, 10 mM MgAcetate and [γ-³³P-ATP] (specific activityapprox. 500 cpm/pmol, concentration as required). The reaction isinitiated by the addition of the MgATP mix. After incubation for 40minutes at room temperature, the reaction is stopped by the addition of3% phosphoric acid solution. 10 μL of the reaction is then spotted ontoa P30 filtermat and washed three times for 5 minutes in 75 mM phosphoricacid and once in methanol prior to drying and scintillation counting.

FLT3 (h)

FLT3 (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 50 μMEAIYAAPFAKKK, 10 mM MgAcetate and [γ-³³P-ATP] (specific activity approx.500 cpm/pmol, concentration as required). The reaction is initiated bythe addition of the MgATP mix. After incubation for 40 minutes at roomtemperature, the reaction is stopped by the addition of 3% phosphoricacid solution. 10 μL of the reaction is then spotted onto a P30filtermat and washed three times for 5 minutes in 75 mM phosphoric acidand once in methanol prior to drying and scintillation counting.

Aurora-A (h)

Aurora-A (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 200 μMLRRASLG (Kemptide), 10 mM MgAcetate and [γ-³³P-ATP] (specific activityapprox. 500 cpm/pmol, concentration as required). The reaction isinitiated by the addition of the MgATP mix. After incubation for 40minutes at room temperature, the reaction is stopped by the addition of3% phosphoric acid solution. 10 μL of the reaction is then spotted ontoa P30 filtermat and washed three times for 5 minutes in 75 mM phosphoricacid and once in methanol prior to drying and scintillation counting.

Aurora-B (h)

Aurora-B (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 30 μMAKRRRLSSLRA, 10 mM MgAcetate and [γ-³³PATP] (specific activity approx.500 cpm/pmol, concentration as required). The reaction is initiated bythe addition of the MgATP mix. After incubation for 40 minutes at roomtemperature, the reaction is stopped by the addition of a 3% phosphoricacid solution. 10 μL of the reaction is then spotted onto a P30filtermat and washed three times for 5 minutes in 75 mM phosphoric acidand once in methanol prior to drying and scintillation counting.

The kinase assays described herein were performed at Millipore UK Ltd,Dundee Technology Park, Dundee DD2 1SW, UK.

Alternatively, the kinase activities of the compounds can be measuredusing KINOMEscan™, which is based on a competition binding assay thatquantitatively measures the ability of a compound to compete with animmobilized, active-site directed ligand. The assay was performed bycombining three components: DNA-tagged kinase; immobilized ligand; and atest compound. The ability of the test compound to compete with theimmobilized ligand was measured via quantitative PCR of the DNA tag.

For most assays, kinase-tagged T7 phage strains were prepared in an E.coli host derived from the BL21 strain. E. coli were grown to log-phaseand infected with T7 phage and incubated with shaking at 32° C. untillysis. The lysates were centrifuged and filtered to remove cell debris.The remaining kinases were produced in HEK-293 cells and subsequentlytagged with DNA for qPCR detection. Streptavidin-coated magnetic beadswere treated with biotinylated small molecule ligands for 30 minutes atroom temperature to generate affinity resins for kinase assays. Theliganded beads were blocked with excess biotin and washed with blockingbuffer (SEABLOCK™ (Pierce), 1% BSA, 0.05% TWEEN®20, 1 mM DTT) to removeunbound ligand and to reduce nonspecific binding. Binding reactions wereassembled by combining kinases, liganded affinity beads, and testcompounds in 1× binding buffer (20% SEABLOCK™, 0.17×PBS, 0.05% TWEEN®20,6 mM DTT). All reactions were performed in polystyrene 96-well plates ina final volume of 0.135 mL. The assay plates were incubated at roomtemperature with shaking for 1 hour and the affinity beads were washedwith wash buffer (1×PBS, 0.05% TWEEN®20). The beads were thenre-suspended in elution buffer (lx PBS, 0.05% TWEEN®20, 0.5 μMnon-biotinylated affinity ligand) and incubated at room temperature withshaking for 30 minutes. The kinase concentration in the eluates wasmeasured by qPCR.

The kinase activity assays described herein can be performed usingKINOMEscan™ Profiling Service at DiscoveRx Corporation, 42501 Albrae St.Fremont, Calif. 94538, USA.

The compounds disclosed herein displayed inhibitory activities againstJAK1, JAK2, JAK3, TYK2, Aurora-A, Aurora-B and/or FLT3 kinases in thecorresponding kinase assays. Especially those compounds shown potentinhibitory activities against JAK1, Aurora-A and Aurora-B. Exemplaryassay results from compounds disclosed herein are listed in Table 5 andTable 6.

Table 5 listed the IC₅₀s of some compounds described herein in the JAK1and Aurora-A kinase assays. Table 6 listed the IC₅₀s of some compoundsdescribed herein in the JAK2, Aurora-B and FLT3 kinases assays.

TABLE 5 JAK1 and Aurora-A Kinase inhibition data IC₅₀ (nM) Example #JAK1 (h) Aurora-A (h) Ex. 1 10 58 Ex. 2 2 28 Ex. 7 0.6 8 Ex. 10 <0.3 4Ex. 12 12 17 Ex. 13 NT 5 Ex. 14 6 21 Ex. 15 8 10 Ex. 16 32 NT Ex. 17 NT6 Ex. 18 12 11 Ex. 19 23 8 Ex. 24 2 3 Ex. 31 NT 50 Ex. 34 3 1 Ex. 37 271 Ex. 38 1 0.8 Ex. 39 2 2 Ex. 40 NT 12 Ex. 41 NT 19 Ex. 43 NT 9 Ex. 44NT 5 Ex. 45 NT 5 Ex. 46 NT 10 Ex. 47 NT 7 NT: Not Test

TABLE 6 JAK2, Aurora-B and FLT3 Kinase inhibition data IC₅₀ (nM) Example# JAK2 (h) Aurora-B (h) FLT3 (h) Ex. 7  20 NT NT Ex. 10  16 NT NT Ex. 15136 2  503 Ex. 18 142 2 1025 Ex. 19 NT 1 NT Ex. 24 NT 0.7 NT Ex. 34 NT0.8 NT Ex. 37 131 NT NT Ex. 38 NT 1 NT Ex. 39 NT 1 NT Ex. 44 NT 1 NT Ex.45 NT 0.8 NT Ex. 46 NT 1 NT Ex. 47 NT 0.6 NT NT: Not Test

Finally, it should be noted that there are alternative ways ofimplementing the present invention. Accordingly, the present embodimentsare to be considered as illustrative and not restrictive and theinvention is not be limited to the details given herein, but may bemodified within the scope and equivalents of the appended claims. Allpublications and patents cited herein are incorporated by reference.

What is claimed is:
 1. A compound having Formula (II):

or a stereoisomer, a tautomer, an N-oxide, a solvate, a pharmaceuticallyacceptable salt or a prodrug thereof, wherein: W is C₇-C₁₂ spirobicycloalkyl, C₇-C₁₂ fused bicycloalkyl, 7-12 membered spiroheterobicyclyl or 7-12 membered fused heterobicycloalkyl, wherein W issubstituted by 1, 2, 3, 4 or 5 R¹⁴ groups; W₁ is H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxyl, C₁-C₆ aminoalkyl, C₁-C₆ hydroxyalkyl, C₃-C₆cycloalkyl or 4-7 membered heterocyclyl; R¹² is H, F, Cl, Br, I, N₃, CN,—NO₂, C₁-C₁₂ alkyl, C₁-C₁₂ alkoxyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,C₃-C₁₂ cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryl, 5-12membered heteroaryl, —NR^(15a)R^(15b), —OR^(15c), —C(═O)OR^(15c),—C(═O)NR^(15a)R^(15b) or —S(═O)₂NR^(15a)R^(15b), wherein each of theC₁-C₁₂ alkyl, C₁-C₁₂ alkoxyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryl and 5-12 memberedheteroaryl is optionally independently substituted by 1, 2, 3, 4 or 5R¹⁷ groups; each R¹³ is independently H, F, Cl, CN, C₁-C₁₂ alkyl, C₂-C₁₂alkenyl, C₁-C₁₂ alkoxyl, —(C₀-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₀-C₄alkylene)-(3-12 membered heterocyclyl), C₆-C₁₂ aryl or 5-12 memberedheteroaryl, wherein each of the C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₁-C₁₂alkoxyl, —(C₀-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₀-C₄ alkylene)-(3-12membered heterocyclyl), C₆-C₁₂ aryl and 5-12 membered heteroaryl isoptionally independently substituted by 1, 2, 3, 4 or 5 R¹⁷ groups; eachR¹⁴ is independently F, Cl, Br, I, NO₂, N₃, CN, C₃-C₁₂ alkyl, C₂-C₁₂alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂ hydroxyalkyl, C₃-C₁₂ alkoxyl, C₁-C₁₂alkylamino, C₁-C₁₂ aminoalkyl, C₃-C₁₂ cycloalkyl, 4-7 memberedheterocyclyl, C₆-C₁₂ aryl, 6-cyanopyridazine-3-yl, —CH₂CN, —CH₂CH₂CN,—C(═O)R^(16d), —S(═O)₂R^(16e), —C(═O)NR^(16a)R^(16b),—S(═O)₂NR^(16a)R^(16b), —C(═O)O—R^(16c), —N(R^(16a))C(═O)R^(16f),—N(R^(16a))S(═O)₂R^(16g) or —OC(═O)R^(16f), wherein each of the —CH₂CN,—CH₂CH₂CN, C₃-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂hydroxyalkyl, C₃-C₁₂ alkoxyl, C₁-C₁₂ alkylamino, C₁-C₁₂ aminoalkyl,C₃-C₁₂ cycloalkyl, 4-7 membered heterocyclyl, C₆-C₁₂ aryl and6-cyanopyridazine-3-yl is optionally independently substituted by 1, 2,3, 4 or 5 R¹⁷ groups; each R^(15a), R^(15b), R^(15e), R^(16a) andR^(16b) is independently H, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂alkynyl, C₃-C₁₂ cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryl,5-12 membered heteroaryl, —(C₁-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄alkylene)-(3-12 membered heterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl),or —(C₁-C₄ alkylene)-(5-12 membered heteroaryl), or R^(15a) and R^(15b),taken together with the nitrogen atom to which they are attached form a3-12 membered heterocyclyl group, wherein each of the C₁-C₁₂ alkyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, 3-12 memberedheterocyclyl, C₆-C₁₂ aryl, 5-12 membered heteroaryl, —(C₁-C₄alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄ alkylene)-(3-12 memberedheterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl), and —(C₁-C₄alkylene)-(5-12 membered heteroaryl) is optionally substituted by 1, 2or 3 substitutents independently selected from F, Cl, Br, CN, N₃, —NO₂,—OH, —NH₂, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄hydroxyalkyl, C₁-C₄ aminoalkyl and C₁-C₄ alkylamino; each R^(16d),R^(16e) and R^(16g) is independently C₂-C₁₂ alkyl, C₃-C₁₂ cycloalkyl,3-12 membered heterocyclyl, C₆-C₁₂ aryl, 5-12 membered heteroaryl,—(C₁-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄ alkylene)-(3-12 memberedheterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl) or —(C₁-C₄alkylene)-(5-12 membered heteroaryl), wherein each of the abovesubstituents is optionally substituted by 1, 2, 3 or 4 substitutentsindependently selected from F, Cl, Br, CN, N₃, —OH, —NH₂, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ hydroxyalkyl, C₁-C₄ aminoalkyl andC₁-C₄ alkylamino; each R^(16c) and R^(16f) is independently C₁-C₃ alkyl,C₃-C₁₂ cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryl, 5-12membered heteroaryl, —(C₁-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄alkylene)-(3-12 membered heterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl),or —(C₁-C₄ alkylene)-(5-12 membered heteroaryl), wherein each of theabove substituents is optionally substituted by 1, 2, 3 or 4substitutents independently selected from F, Cl, Br, CN, N₃, —OH, —NH₂,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ hydroxyalkyl, C₁-C₄aminoalkyl and C₁-C₄ alkylamino; each R¹⁷ is independently F, Cl, Br, I,CN, NO₂, N₃, —OH, —NH₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆haloalkyl, C₃-C₆ cycloalkyl, C₆-C₁₂ aryl, 4-7 membered heterocyclyl,5-12 membered heteroaryl, C₁-C₆ aminoalkyl, C₁-C₆ alkylamino, C₁-C₆alkoxyl, C₁-C₆ hydroxyalkyl, —NH(C₀-C₄ alkylene)-(C₃-C₆ cycloalkyl),—NH(C₀-C₄ alkylene)-(4-7 membered heterocyclyl), —N[(C₀-C₄alkylene)-(C₃-C₆ cycloalkyl)]2, —N[(C₀-C₄ alkylene)-(4-7 memberedheterocyclyl)]₂, —O(C₀-C₄ alkylene)-(C₃-C₆ cycloalkyl) or —O(C₀-C₄alkylene)-(4-7 membered heterocyclyl); and n is 0, 1 or
 2. 2. Thecompound of claim 1, wherein W is 8-11 membered spiro heterobicyclyl or8-10 membered fused heterobicycloalkyl, wherein W is substituted by 1,2, 3 or 4 R¹⁴ groups.
 3. The compound of claim 1, wherein W is:

or a stereoisomer thereof, wherein each Y, Y′, Y² and Y³ isindependently —CH₂—, —NH— or —O—, with the proviso that Y² and Y³ arenot —O— simultaneously; and wherein W is substituted by 1, 2 or 3 R¹⁴groups.
 4. The compound of claim 1, wherein W is:

or a stereoisomer thereof, and wherein W is substituted by 1, 2 or 3 R¹⁴groups.
 5. The compound of claim 1, wherein W₁ is H, methyl, ethyl,n-propyl, isopropyl or cyclopropyl.
 6. The compound of claim 1, whereinR¹² is H, F, Cl, Br, I, N₃, CN, —NO₂, C₁-C₄ alkyl, C₁-C₄ alkoxyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, 4-7 membered heterocyclyl,—NR^(15a)R^(15b), —OR^(15c), —C(═O)OR^(15c), —C(═O)NR^(15a)R^(15b) or—S(═O)₂NR^(15a)R^(15b), wherein each of the C₁-C₄ alkyl, C₁-C₄ alkoxyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl and 4-7 memberedheterocyclyl is optionally independently substituted by 1, 2 or 3 R¹⁷groups.
 7. The compound of claim 1, wherein each R¹³ is independently H,F, Cl, CN, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxyl, —(C₀-C₃alkylene)-(C₃-C₆ cycloalkyl) or —(C₀-C₃ alkylene)-(4-7 memberedheterocyclyl), wherein each of the C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄alkoxyl, —(C₀-C₃ alkylene)-(C₃-C₆ cycloalkyl) and —(C₀-C₃ alkylene)-(4-7membered heterocyclyl) is optionally independently substituted by 1, 2or 3 R¹⁷ groups.
 8. The compound of claim 1, wherein each R¹⁴ isindependently F, Cl, Br, I, —NO₂, N₃, CN, C₃-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₆ hydroxyalkyl, C₃-C₆ alkoxyl, C₁-C₆ alkylamino,C₁-C₆ aminoalkyl, C₃-C₆ cycloalkyl, 4-7 membered heterocyclyl, phenyl,6-cyanopyridazine-3-yl, —CH₂CN, —CH₂CH₂CN, —C(═O)R^(16d),—S(═O)₂R^(16e), —C(═O)NR^(16a)R^(16b), —S(═O)₂NR^(16a)R^(16b),—C(═O)O—R^(16c), —N(R^(16a))C(═O)R^(16f), —N(R^(16a))S(═O)₂R^(16g) or—OC(═O)R^(16f), wherein each of the —CH₂CN, —CH₂CH₂CN, C₃-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ hydroxyalkyl, C₃-C₆ alkoxyl, C₁-C₆alkylamino, C₁-C₆ aminoalkyl, C₃-C₆ cycloalkyl, 4-7 memberedheterocyclyl, phenyl and 6-cyanopyridazine-3-yl is optionallyindependently substituted by 1, 2 or 3 R¹⁷ groups.
 9. The compound ofclaim 1, wherein each R¹⁴ is independently F, Cl, Br, —NO₂, CN,


10. The compound of claim 1, wherein each R^(15a), R^(15b), R^(15c),R^(16a) and R^(16b) is independently H, C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6membered heteroaryl, —(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl), —(C₁-C₃alkylene)-(4-7 membered heterocyclyl), —(C₁-C₃ alkylene)-phenyl or—(C₁-C₃ alkylene)-(5-6 membered heteroaryl), or R^(15a) and R^(15b),taken together with the nitrogen atom to which they are attached form a4-7 membered heterocyclyl group, wherein each of the C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, 4-7 membered heterocyclyl,phenyl, 5-6 membered heteroaryl, —(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl),—(C₁-C₃ alkylene)-(4-7 membered heterocyclyl), —(C₁-C₃ alkylene)-phenyland —(C₁-C₃ alkylene)-(5-6 membered heteroaryl) is optionallysubstituted by 1, 2 or 3 substitutents independently selected from F,Cl, Br, CN, N₃, —NO₂, —OH, —NH₂, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃alkoxy, C₁-C₃ hydroxyalkyl, C₁-C₃ aminoalkyl and C₁-C₃ alkylamino. 11.The compound of claim 1, wherein each R^(16d), R^(16e) and R^(16g) isindependently C₂-C₆ alkyl, C₃-C₆ cycloalkyl, 4-7 membered heterocyclyl,phenyl, 5-6 membered heteroaryl, —(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl),—(C₁-C₃ alkylene)-(4-7 membered heterocyclyl), —(C₁-C₃ alkylene)-phenyl,or —(C₁-C₃ alkylene)-(5-6 membered heteroaryl), wherein each of theabove substituents is optionally substituted by 1, 2, 3 or 4substitutents independently selected from F, Cl, Br, CN, N₃, —OH, —NH₂,C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃ hydroxyalkyl, C₁-C₃aminoalkyl and C₁-C₃ alkylamino.
 12. The compound of claim 1, whereineach R^(16c) and R^(16f) is independently C₁-C₃ alkyl, C₃-C₆ cycloalkyl,4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, —(C₁-C₃alkylene)-(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)-(4-7 memberedheterocyclyl), —(C₁-C₃ alkylene)-phenyl, or —(C₁-C₃ alkylene)-(5-6membered heteroaryl), wherein each of the above substituents isoptionally substituted by 1, 2, 3 or 4 substitutents independentlyselected from F, Cl, Br, CN, N₃, —OH, —NH₂, C₁-C₃ alkyl, C₁-C₃haloalkyl, C₁-C₃ alkoxy, C₁-C₃ hydroxyalkyl, C₁-C₃ aminoalkyl and C₁-C₃alkylamino.
 13. The compound of claim 1 having one of the followingstructures:

a stereoisomer, a tautomer, an N-oxide, a solvate, or a pharmaceuticallyacceptable salt thereof.
 14. A pharmaceutical composition comprising thecompound of claim 1, and a pharmaceutically acceptable excipient,carrier, adjuvant, vehicle or a combination thereof.
 15. Thepharmaceutical composition of claim 14 further comprising a therapeuticagent selected from the group consisting of chemotherapeutic agents,anti-proliferative agents, phosphodiesterase 4 (PDE4) inhibitors,β₂-adrenoreceptor agonists, corticosteroids, non-steroidal GR agonists,anticholinergic agents, antihistamines, anti-inflammatory agents,immunosuppressants, immunomodulators, agents for treatingatherosclerosis, agents for treating pulmonary fibrosis and combinationsthereof.
 16. A method of managing, treating or lessening the severity ofa protein kinase-mediated disease in a patient by administering to thepatient the compound of claim 1, wherein the protein kinase is selectedfrom JAK1, JAK2, Aurora A, Aurora B and FLT3, and wherein the disease isa cancer selected from head and neck cancer, prostate cancer, breastcancer, ovarian cancer, melanoma, lung cancer, brain tumor, pancreaticcancer and renal carcinoma; or wherein the disease is selected frompolycythemia vera, essential thrombocytosis, myelofibrosis, chronicmyelogenous leukemia (CML), acute myeloid leukemia (AML), acutelymphocytic leukemia (ALL), chronic obstruction pulmonary disease(COPD), asthma, systemic lupus erythematosis, cutaneous lupuserythematosis, lupus nephritis, dermatomyositis, Sjogren's syndrome,psoriasis, type I diabetes mellitus, allergic airway disease, sinusitis,eczema, hives, food allergies, allergies to insect venom, inflammatorybowel syndrome, Chron's disease, rheumatoid arthritis, juvenilearthritis and psoriatic arthritis, or a graft-versus-host diseaseselected from organ transplant rejection, tissue transplant rejectionand cell transplant rejection.
 17. A method of managing, treating orlessening the severity of a protein kinase-mediated disease in a patientby administering to the patient the pharmaceutical composition of claim14, wherein the protein kinase is selected from JAK1, JAK2, Aurora A,Aurora B and FLT3, and wherein the disease is a cancer selected fromhead and neck cancer, prostate cancer, breast cancer, ovarian cancer,melanoma, lung cancer, brain tumor, pancreatic cancer and renalcarcinoma; or wherein the disease is selected from polycythemia vera,essential thrombocytosis, myelofibrosis, chronic myelogenous leukemia(CML), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL),chronic obstruction pulmonary disease (COPD), asthma, systemic lupuserythematosis, cutaneous lupus erythematosis, lupus nephritis,dermatomyositis, Sjogren's syndrome, psoriasis, type I diabetesmellitus, allergic airway disease, sinusitis, eczema, hives, foodallergies, allergies to insect venom, inflammatory bowel syndrome,Chron's disease, rheumatoid arthritis, juvenile arthritis and psoriaticarthritis, or a graft-versus-host disease selected from organ transplantrejection, tissue transplant rejection and cell transplant rejection.18. A method of inhibiting the activity of a protein kinase with thecompound of claim 1, wherein the protein kinase is JAK kinase, FLT3kinase, Aurora kinase or a combination thereof.
 19. A method ofinhibiting the activity of a protein kinase with the pharmaceuticalcomposition of claim 14, wherein the protein kinase is JAK kinase, FLT3kinase, Aurora kinase or a combination thereof.